Estimating the efficacy of pharmacogenomics over a lifetime.

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.

Validating cuffless continuous blood pressure monitoring devices.

Cuff-based home blood pressure (BP) devices, which have been the standard for BP monitoring for decades, are limited by physical discomfort, convenience, and their ability to capture BP variability and patterns between intermittent readings. In recent years, cuffless BP devices, which do not require cuff inflation around a limb, have entered the market, offering the promise of continuous beat-to-beat measurement of BP. These devices take advantage of a variety of principles to determine BP, including (1) pulse arrival time, (2) pulse transit time, (3) pulse wave analysis, (4) volume clamping, and (5) applanation tonometry. Because BP is calculated indirectly, these devices require calibration with cuff-based devices at regular intervals. Unfortunately, the pace of regulation of these devices has failed to match the speed of innovation and direct availability to patient consumers. There is an urgent need to develop a consensus on standards by which cuffless BP devices can be tested for accuracy. In this narrative review, we describe the landscape of cuffless BP devices, summarize the current status of validation protocols, and provide recommendations for an ideal validation process for these devices.

Medical records-based chronic kidney disease phenotype for clinical care and "big data" observational and genetic studies.

Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.

Evaluating the impact of motion artifact on noninvasive blood pressure devices.

Most automated sphygmomanometers use oscillometric algorithms. Motion, either patient-based or environmental, will affect the ability of a device to record an accurate blood pressure (BP). Members of the Association for the Advancement of Medical Instrumentation (AAMI) Sphygmomanometer Committee have been studying this problem for more than a decade. The AAMI TIR44 was the first publication to address the challenges of motion tolerance. The concepts described in TIR44 have led to the development of a draft of ISO 81060-4, a new standard for testing devices for which the manufacturer wishes to claim motion tolerance. The current ISO 81060-2 addresses both stress testing and 24-hour ambulatory BP monitoring. Recent publications have reported on testing of devices in response to voluntary and involuntary patient motion. The ISO 81060-4 will address testing in the presence of patient transport by ground, fixed-wing, and rotary (helicopter) ambulances. The protocol will utilize noise profiles recorded under those three conditions. The profiles will be digitally stored on a library with free access. The proposed testing will be performed using patient simulators introducing the noise library files into known BP oscillometric envelopes. The specifications of the data capture and playback devices are specified, as is the evaluation statistical testing. The authors expect that the final draft will be published in 2020.

Treatment-Related Cardiovascular Outcomes in Patients with Symptomatic Subclavian Artery Stenosis.

BACKGROUND: Subclavian artery stenosis (SAS) is narrowing of the subclavian artery most commonly caused by atherosclerosis. It serves as a marker for cerebrovascular and myocardial ischemic events. METHODS: A retrospective cohort study was conducted to determine the association of treatment via combination therapy (antiplatelet drug plus either by-pass surgery or percutaneous transluminal angioplasty (PTA) with or without stent implantation) versus antiplatelet drug therapy alone on cardiovascular events and all-cause mortality in Marshfield Clinic patients diagnosed with symptomatic SAS from January 1, 1995 to December 31, 2009. RESULTS: Of the total 2153 cases, 100 patients were identified as eligible to be included in the study. Of these 100 patients that met inclusion criteria, 30 underwent combination therapy while 70 were managed only with drug treatment. A median length of follow-up was 8.45 years. Adverse cardiovascular events occurred in 5/30 (17%) of combination therapy patients compared to 28/70 (40%) of antiplatelet drug therapy only patients (p = 0.0355). Accordingly, all-cause mortality was higher (47%) in the antiplatelet drug therapy only group than the combination therapy group (13%) [hazard ratio = 3.45, p = 0.0218]. CONCLUSIONS: Preliminary findings in this pilot data set suggest that combination therapy (medications plus either surgical or interventional repair) of subclavian artery stenosis is associated with less cardiovascular adverse events and higher survival rates. However, prospective randomized studies with larger number of patients are needed to validate these findings.

Evaluating electronic health record data sources and algorithmic approaches to identify hypertensive individuals.

OBJECTIVE: Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often iterative, depends on fallible investigator intuition, and is time- and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites. MATERIALS AND METHODS: We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best-performing algorithms at the Marshfield Clinic. RESULTS: Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non-NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar. CONCLUSION: This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision.

A Robust e-Epidemiology Tool in Phenotyping Heart Failure with Differentiation for Preserved and Reduced Ejection Fraction: the Electronic Medical Records and Genomics (eMERGE) Network.

Identifying populations of heart failure (HF) patients is paramount to research efforts aimed at developing strategies to effectively reduce the burden of this disease. The use of electronic medical record (EMR) data for this purpose is challenging given the syndromic nature of HF and the need to distinguish HF with preserved or reduced ejection fraction. Using a gold standard cohort of manually abstracted cases, an EMR-driven phenotype algorithm based on structured and unstructured data was developed to identify all the cases. The resulting algorithm was executed in two cohorts from the Electronic Medical Records and Genomics (eMERGE) Network with a positive predictive value of >95 %. The algorithm was expanded to include three hierarchical definitions of HF (i.e., definite, probable, possible) based on the degree of confidence of the classification to capture HF cases in a whole population whereby increasing the algorithm utility for use in e-Epidemiologic research.

Public-use blood pressure measurement: the kiosk quandary.

It is important to note the opportunity that validated public-use kiosks offer the U.S. healthcare system in terms of ease of public access, reduced cost of screening/monitoring, and the opportunity to support coordinated care between physicians, pharmacists, and patients. It is equally important to recognize that all public-use BP kiosks are not equivalent. Members of the AAMI Sphygmomanometer Committee and other ''concerned citizens'' are working with FDA officials to try to improve both device validation and cuff range performance of these devices. In reality, regulatory changes will be slow to take effect, and for the foreseeable future, the burden of device accuracy assessment lies with the private sector and the public. There is a device currently available that has undergone full validation testing and offers a wide-range cuff validated for almost all US adult arms. We recognize the importance of innovation in out-of-office BP measurement. Therefore, in the interest of public health, we strongly urge those business professionals buying such devices, and those health professionals advising patients on their use, to become better informed and more discriminant in their device selection.

Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT.

BACKGROUND: Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD. OBJECTIVES: To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT). DESIGN: Randomized, double-blind, active-control trial in high-risk hypertensive participants. PARTICIPANTS: Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT. INTERVENTIONS/EVENTS: In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years. MAIN MEASURES: Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups. KEY RESULTS: Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality. CONCLUSIONS: Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Blood pressure control and cardiovascular outcomes in normal-weight, overweight, and obese hypertensive patients treated with three different antihypertensives in ALLHAT.

OBJECTIVE: Epidemiologically, there is a strong relationship between BMI and blood pressure (BP) levels. We prospectively examined randomization to first-step chlorthalidone, a thiazide-type diuretic; amlodipine, a calcium-channel blocker; and lisinopril, an angiotensin-converting enzyme inhibitor, on BP control and cardiovascular outcomes in a hypertensive cohort stratified by baseline BMI [kg/m(2); normal weight (BMI <25), overweight (BMI = 25-29.9), and obese (BMI >30)]. METHODS: In a randomized, double-blind, practice-based Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, 33,357 hypertensive participants, aged at least 55 years, were followed for an average of 4.9 years, for a primary outcome of fatal coronary heart disease or nonfatal myocardial infarction, and secondary outcomes of stroke, heart failure, combined cardiovascular disease, mortality, and renal failure. RESULTS: Of participants, 37.9% were overweight and 42.1% were obese at randomization. For each medication, BP control (<140/90 mmHg) was equivalent in each BMI stratum. At the fifth year, 66.1, 66.5, and 65.1% of normal-weight, overweight, and obese participants, respectively, were controlled. Those randomized to chlorthalidone had highest BP control (67.2, 68.3, and 68.4%, respectively) and to lisinopril the lowest (60.4, 63.2, and 59.6%, respectively) in each BMI stratum. A significant interaction (P = 0.004) suggests a lower coronary heart disease risk in the obese for lisinopril versus chlorthalidone (hazard ratio 0.85, 95% confidence interval 0.74-0.98) and a significant interaction (P = 0.011) suggests a higher risk of end-stage renal disease for amlodipine versus chlorthalidone in obese participants (hazard ratio 1.49, 95% confidence interval 1.06-2.08). However, these results were not consistent among other outcomes. CONCLUSION: BMI status does not modify the effects of antihypertensive medications on BP control or cardiovascular disease outcomes.

Formation of community-based hypertension practice networks: success, obstacles, and lessons learned.

Community-based practice networks for research and improving the quality of care are growing in size and number but have variable success rates. In this paper, the authors review recent efforts to initiate a community-based hypertension network modeled after the successful Outpatient Quality Improvement Network (O'QUIN) project, located at the Medical University of South Carolina. Key lessons learned and new directions to be explored are highlighted.

The use of dietary supplements and their association with blood pressure in a large Midwestern cohort.

BACKGROUND: There have been numerous studies assessing the association of diet and blood pressure but little is known about the association between less commonly used nutritional supplements and blood pressured. The purpose of this study was to quantify the use of dietary supplements and their potential association with blood pressure in a large population-based cohort of adults in the Midwest. METHODS: The Personalized Medicine Research Project cohort was the population source for the current study. The current study includes subjects with Dietary History Questionnaire (DHQ) data available as well as at least one clinical blood pressure measurement recorded in their electronic medical record. After excluding extreme outlying measurements, median systolic and diastolic blood pressure measurements were calculated for each individual and were compared for subjects who did and did not report taking one of a list of 37 different supplements listed on the DHQ more than once per week over the previous 12 months. RESULTS: 9,732 subjects had both blood pressure and DHQ data available. They ranged in age from 18 to 98 years (mean 56 years) and 3,625 (37%) were male. Nine of 37 supplements showed evidence for association with blood pressure: coenzyme Q10, fish oil, iron, bilberry, echinacea, evening primrose oil, garlic, goldenseal and milk thistle. With the exception of the mineral iron, mean systolic and diastolic blood pressures were higher for users of the specific supplements than non-users. CONCLUSIONS: These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. We hope the observed significant associations will foster future research to evaluate blood pressure effects of dietary supplements.

Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).

The authors conducted a randomized, controlled, multicenter trial, in which they assigned well-controlled hypertensive participants aged 55 years and older with moderate hypercholesterolemia to receive pravastatin (n=5170) or usual care (n=5185) for 4 to 8 years, when trial therapy was discontinued. Passive surveillance using national databases to ascertain deaths and hospitalizations continued for a total follow-up of 8 to 13 years to assess whether mortality and morbidity differences persisted or new differences developed. During the post-trial period, fatal and nonfatal outcomes were available for 98% and 64% of participants, respectively. The primary outcome was all-cause mortality and the secondary outcomes included cardiovascular mortality, coronary heart disease (CHD), stroke, heart failure, cardiovascular disease, and end-stage renal disease. No significant differences appeared in mortality for pravastatin vs usual care (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03) or other secondary outcomes. Similar to the previously reported in-trial result, there was a significant treatment effect for CHD in black patients (HR, 0.79; 95% CI, 0.64-0.98). However, the in-trial result showing a significant treatment by race effect did not remain significant during the entire follow-up (P=.08). These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in black patients.