Accelerated Epigenetic Aging Is Associated With Multiple Cardiometabolic, Hematologic, and Renal Abnormalities: A Project Baseline Health Substudy.

BACKGROUND: Epigenetic clocks estimate chronologic age using methylation levels at specific loci. We tested the hypothesis that accelerated epigenetic aging is associated with abnormal values in a range of clinical, imaging, and laboratory characteristics. METHODS: The Project Baseline Health Study recruited 2502 participants, including 1661 with epigenetic age estimates from the Horvath pan-tissue clock. We classified individuals with extreme values as having epigenetic age acceleration (EAA) or epigenetic age deceleration. A subset of participants with longitudinal methylation profiling was categorized as accelerated versus nonaccelerated. Using principal components analysis, we created phenoclusters using 122 phenotypic variables and compared individuals with EAA versus epigenetic age deceleration, and at one year of follow-up, using logistic regression models adjusted for sex (false discovery rate [Q] <0.10); in secondary exploratory analyses, we tested individual clinical variables. RESULTS: The EAA (n=188) and epigenetic age deceleration (n=195) groups were identified as having EAA estimates ≥5 years or ≤-5 years, respectively. In primary analyses, individuals with EAA had higher values for phenoclusters summarizing lung function and lipids, and lower values for a phenocluster representing physical function. In secondary analyses of individual variables, neutrophils, body mass index, and waist circumference were significantly higher in individuals with EAA (Q<0.10). No phenoclusters were significantly different between participants with accelerated (n=148) versus nonaccelerated (n=112) longitudinal aging. CONCLUSIONS: We report multiple cardiometabolic, hematologic, and physical function features characterizing individuals with EAA. These highlight factors that may mediate the adverse effects of aging and identify potential targets for study of mitigation of these effects. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03154346.

The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study: design, methods, and baseline characteristics.

OBJECTIVES: Coronavirus Disease 2019 (COVID-19) is a viral illness with public health importance. The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study is a prospective, longitudinal cohort study designed to contribute valuable information on community prevalence of active COVID-19 infection and SARS-CoV-2 antibodies as the pandemic and responses to it have and continue to evolve. We present the rationale, study design, and baseline characteristics of the C3PI Study. METHODS: We recruited 1,426 participants between June 2020 and August 2020 from the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository, a previously established, community-based, longitudinal cohort. Participants completed a baseline survey and follow-up surveys every two weeks. A nested weighted, random sub-cohort (n=300) was recruited to measure the incidence and prevalence of active COVID-19 infection and SARS-CoV-2 IgG antibodies. RESULTS: The sub-cohort was younger (56 vs 61 years), had more men (39.0% vs 30.9%), and a higher proportion of Hispanic (11.0% vs 5.1%) and Black participants (17.0% vs 8.2%) compared with the overall cohort. They had similar anthropometrics and medical histories, but a greater proportion of the sub-cohort had a higher educational degree (36.1% vs 31.3%) and reported a pre-pandemic annual household income of >$90,000 (57.1% vs 47.9%). CONCLUSION: This study is part of a multisite consortium that will provide critical data on the epidemiology of COVID-19 and community perspectives about the pandemic, behaviors and mitigation strategies, and individual and community burden in North Carolina.

Return of individual research results: What do participants prefer and expect?

Newer data platforms offer increased opportunity to share multidimensional health data with research participants, but the preferences of participants for which data to receive and how is evolving. Our objective is to describe the preferences and expectations of participants for the return of individual research results within Project Baseline Health Study (PBHS). The PBHS is an ongoing, multicenter, longitudinal cohort study with data from four initial enrollment sites. PBHS participants are recruited from the general population along with groups enriched for heart disease and cancer disease risk. Cross-sectional data on return of results were collected in 2017-2018 from an (1) in-person enrollment survey (n = 1,890), (2) benchmark online survey (n = 1,059), and (3) participant interviews (n = 21). The main outcomes included (1) preferences for type of information to be added next to returned results, (2) participant plans for sharing returned results with a non-study clinician, and (3) choice to opt-out of receiving genetic results. Results were compared by sociodemographic characteristics. Enrollment and benchmark survey respondents were 57.1% and 53.5% female, and 60.0% and 66.2% white, respectively. Participants preferred the following data types be added to returned results in the future: genetics (29.9%), heart imaging, (16.4%), study watch (15.8%), and microbiome (13.3%). Older adults (OR 0.60, 95% CI: 0.41-0.87) were less likely to want their genetic results returned next. Forty percent of participants reported that they would not share all returned results with their non-study clinicians. Black (OR 0.64, 95% CI 0.43-0.95) and Asian (OR 0.47, 95% CI 0.30-0.73) participants were less likely, and older participants more likely (OR 1.45-1.61), to plan to share all results with their clinician than their counterparts. At enrollment, 5.8% of participants opted out of receiving their genetics results. The study showed that substantial heterogeneity existed in participant's preferences and expectations for return of results, and variations were related to sociodemographic characteristics.

Lipid changes in the metabolome of a single case study with maple syrup urine disease (MSUD) after five days of improved diet adherence of controlled branched-chain amino acids (BCAA).

BACKGROUND: Distinguishing systemic metabolic disruptions in maple syrup urine disease (MSUD) beyond amino acid pathways is under-investigated, yet important to understanding disease pathology and treatment options. METHODS: An adolescent female (15 years) with MSUD without liver transplant, attended 2 study visits, 5 days apart. Medical diet adherence was determined based on her 3-day diet records and plasma branched-chain amino acid (BCAA) concentrations at both study visits. Plasma from a single age- and sex-matched control (MURDOCK Study, Duke University) and the case patient were analyzed with UPLC/MS/MS for intensity (m/z), annotated, and normalized against a median of 1 (Metabolon, Morrisville NC). Differences between case/control and 5-day comparisons were defined as ≥ Ç€ 0.5 ǀ. RESULTS: 434 lipid metabolites were identified across samples; 90 (20.7%) were higher and 120 (27.6%) lower in the MSUD case at baseline compared with control. By study visit 2, plasma BCAA had declined, while 48 (53%) of elevated lipids and 14 (11.7%) of lower lipid values had moved to within ǀ 0.5 ǀ of control. Most shifts towards control by day 5 were seen in long-chain fatty acid intermediates (42%) and acylcarnitines (32%). Although androgenic (28%) and bile acid (23%) metabolites increased towards control, neither reached control level by day 5. DISCUSSION: This comparative metabolomics study in a single MSUD case and healthy control suggests intrinsic differences in MSUD lipid metabolism potentially influenced by therapeutic diet. Findings suggest influences on hormone regulation, fatty acid oxidation, and bile acid synthesis, but further studies are needed to confirm an association between MSUD and lipid dysregulation. SYNOPSIS: Within 5 days of improved dietary adherence, a single MSUD case experienced substantial changes in lipid markers potentially related to changes in plasma branched-chain amino acids.

The Project Baseline Health Study: a step towards a broader mission to map human health.

The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

Culture counts--sustainable inpatient computerized surveillance across Duke University Health System.

PURPOSE: The authors report on the managerial and logistical details of deploying a computerized adverse drug event surveillance system that was at first a grant-funded research project and ultimately was changed to a sustained safety-monitoring application serving 3 different hospitals. METHODS: Surveillance was deployed in 3 phases to 2 community-based hospitals and an academic medical center. A logic-based rules engine surveyed electronic records for laboratory, medication, and demographic information indicative of safety concerns. Potential adverse events triggered manual chart review by pharmacists to verify patient harm. RESULTS: During Phase 1, the research team created trigger rules for each hospital. In Phase 2, the trigger review was transitioned to hospital personnel and rule sets were reshaped for specific hospital needs. In Phase 3, surveillance was integrated into daily work flows and organizational balanced scorecards where it was accepted as a quantitative measure of medication safety performance. DISCUSSION AND CONCLUSION: Computerized surveillance helps detect potentially harmful events regardless of hospital size. Active leadership, change-tolerant culture, and hospital pharmacy practice models significantly impact successful adoption. Entrenched cultural issues impeded sustainability at the academic center but not at the 2 community hospitals. Tailoring surveillance to the needs of different inpatient settings is crucial to developing a sustainable model.

Tailoring adverse drug event surveillance to the paediatric inpatient.

INTRODUCTION: Although paediatric patients have an increased risk for adverse drug events, few detection methodologies target this population. To utilise computerised adverse event surveillance, specialised trigger rules are required to accommodate the unique needs of children. The aim was to develop new, tailored rules sustainable for review and robust enough to support aggregate event rate monitoring. METHODS: The authors utilised a voluntary staff incident-reporting system, lab values and physician insight to design trigger rules. During Phase 1, problem areas were identified by reviewing 5 years of paediatric voluntary incident reports. Based on these findings, historical lab electrolyte values were analysed to devise critical value thresholds. This evidence informed Phase 2 rule development. For 3 months, surveillance alerts were evaluated for occurrence of adverse drug events. RESULTS: In Phase 1, replacement preparations and total parenteral nutrition comprised the majority (36.6%) of adverse drug events in 353 paediatric patients. During Phase 2, nine new trigger rules produced 225 alerts in 103 paediatric inpatients. Of these, 14 adverse drug events were found by the paediatric hypoglycaemia rule, but all other electrolyte trigger rules were ineffective. Compared with the adult-focused hypoglycaemia rule, the new, tailored version increased the paediatric event detection rate from 0.43 to 1.51 events per 1000 patient days. CONCLUSIONS: Relying solely on absolute lab values to detect electrolyte-related adverse drug events did not meet our goals. Use of compound rule logic improved detection of hypoglycaemia. More success may be found in designing real-time rules that leverage lab trends and additional clinical information.

Characteristics of ambulatory anticoagulant adverse drug events: a descriptive study.

BACKGROUND: Despite the high frequency with which adverse drug events (ADEs) occur in outpatient settings, detailed information regarding these events remains limited. Anticoagulant drugs are associated with increased safety concerns and are commonly involved in outpatient ADEs. We therefore sought to evaluate ambulatory anticoagulation ADEs and the patient population in which they occurred within the Duke University Health System (Durham, NC, USA). METHODS: A retrospective chart review of ambulatory warfarin-related ADEs was conducted. An automated trigger surveillance system identified eligible events in ambulatory patients admitted with an International Normalized Ratio (INR) >3 and administration of vitamin K. Event and patient characteristics were evaluated, and quality/process improvement strategies for ambulatory anticoagulation management are described. RESULTS: A total of 169 events in 167 patients were identified from December 1, 2006-June 30, 2008 and included in the study. A median supratherapeutic INR of 6.1 was noted, and roughly half of all events (52.1%) were associated with a bleed. Nearly 74% of events resulted in a need for fresh frozen plasma; 64.8% of bleeds were classified as major. A total of 59.2% of events were at least partially responsible for hospital admission. Median patient age was 68 y (range 36-95 y) with 24.9% initiating therapy within 3 months prior to the event. Of events with a prior documented patient visit (n = 157), 73.2% were seen at a Duke clinic or hospital within the previous month. Almost 80% of these patients had anticoagulation therapy addressed, but only 60.0% had a follow-up plan documented in the electronic note. CONCLUSIONS: Ambulatory warfarin-related ADEs have significant patient and healthcare utilization consequences in the form of bleeding events and associated hospital admissions. Recommendations for improvement in anticoagulation management include use of information technology to assist monitoring and follow-up documentation, avoid drug interactions, and engage patients in their care.

Computerized surveillance of opioid-related adverse drug events in perioperative care: a cross-sectional study.

BACKGROUND: Given the complexity of surgical care, perioperative patients are at high risk of opioid-related adverse drug events. Existing methods of detection, such as trigger tools and manual chart review, are time-intensive which makes sustainability challenging. Using strategic rule design, computerized surveillance may be an efficient, pharmacist-driven model for event detection that leverages existing staff resources. METHODS: Computerized adverse drug event surveillance uses a logic-based rules engine to identify potential adverse drug events or evolving unsafe clinical conditions. We extended an inpatient rule (administration of naloxone) to detect opioid-related oversedation and respiratory depression to perioperative care at a large academic medical center. Our primary endpoint was the adverse drug event rate. For all patients with a naloxone alert, manual chart review was performed by a perioperative clinical pharmacist to assess patient harm. In patients with confirmed oversedation, other patient safety event databases were queried to determine if they could detect duplicate, prior, or subsequent opioid-related events. RESULTS: We identified 419 cases of perioperative naloxone administration. Of these, 101 were given postoperatively and 69 were confirmed as adverse drug events after chart review yielding a rate of 1.89 adverse drug events/1000 surgical encounters across both the inpatient and ambulatory settings. Our ability to detect inpatient opioid adverse drug events increased 22.7% by expanding surveillance into perioperative care. Analysis of historical surveillance data as well as a voluntary reporting database revealed that 11 of our perioperative patients had prior or subsequent harmful oversedation. Nine of these cases received intraoperative naloxone, and 2 had received naloxone in the post-anesthesia care unit. Pharmacist effort was approximately 3 hours per week to evaluate naloxone alerts and confirm adverse drug events. CONCLUSION: A small investment of resources into a pharmacist-driven surveillance model gave great gains in organizational adverse drug event detection. The patients who experienced multiple events are particularly relevant to future studies seeking risk factors for opioid induced respiratory depression. Computerized surveillance is an efficient, impactful, and sustainable model for ongoing capture and analysis of these rare, but potentially serious events.

Reevaluating the safety profile of pediatrics: a comparison of computerized adverse drug event surveillance and voluntary reporting in the pediatric environment.

OBJECTIVES: Children are at exceptionally high risk for adverse drug events. At Duke University Hospital, computerized adverse drug event surveillance and voluntary safety reporting systems work synergistically to identify adverse drug events. Here we identify the most deleterious drug classes to pediatric inpatients and determine which detection methodology provides the greatest opportunity to reduce harm. PATIENTS AND METHODS: We evaluated all of the medication-related events detected by our computerized surveillance and safety reporting systems over a 1-year period for Duke University Hospital pediatric inpatients. Events from both systems were scored for severity and assigned a drug event category. Surveillance events were additionally scored for causality. RESULTS: A total of 849 medication-related reports were entered into the safety reporting system, and 93 caused patient harm, resulting in an adverse drug event rate of 1.8 events per 1000 pediatric patient-days. Seventy eight of the 1537 medication-related events detected by surveillance resulted in patient harm, giving a rate of 1.6 events per 1000 patient-days. The most common events identified by the safety reporting system were failures in the medication use process (26.9%), drug omissions (16.1%), and dose- or rate-related events (12.9%). The most frequent adverse drug event surveillance categories were nephrotoxins (20.7%), narcotics and benzodiazepines (19.3%), and hypoglycemia (11.5%). Most voluntarily reported events originated in ICUs (72.0%), whereas surveillance events were split evenly across intensive and general care. There was little overlap between methodologies. CONCLUSIONS: The epidemiology of pediatric adverse drug events is best addressed by using voluntary reporting in tandem with other strategies, such as computerized surveillance and targeted chart review. Although voluntary reporting excels at identifying administration errors, surveillance excels at detecting adverse drug events caused by high-risk medications and identifies evolving conditions that may provoke imminent patient harm. Surveillance underperformed in pediatrics when compared with adult detection rates, suggesting that tailored rules may be necessary for a robust pediatric adverse drug event surveillance system.