Robert H. Christenson

Object: Transdermal biosensors may provide an alternative to conventional blood-based biomarker measurement. Our purpose was to determine the binary correlation between transdermal (Infrasensor; RCE, Inc, Carlsbad, CA) and conventional blood-based measurements. Methods: This was a secondary analysis from a previously published observational cardiac troponin I (cTnI) study performed to establish the upper reference level of cTnI, at 10 US hospitals. After obtaining informed consent, 2 cohorts of patients were enrolled: 1) those who completed a health assessment questionnaire and appeared healthy, and 2) those with a known elevated cTnI per the local hospital standard assay. All blood lab analyses were performed at the University of Maryland Medical Center, Baltimore, MD. Normal was defined as cTnI 0.95 mg/dL (female), and HbA1c <6.4%. The Infrasensor was placed on the patient's wrist for measurement and blood drawn for analysis at approximately the same time. Results: Of 840 enrolled patients, the median (IQR) age was 46 (30,57), 416 (49.5%) were female, 10.36% Hispanic, 6.7% Asian, 12.9% African American, and 69.1% White. Elevated lab tests were 102 hscTnI's, 156 NTproBNP's, 37 HbA1C's, and 163 creatinine's. Significant binary correlations were found between all transdermal signals and the corresponding lab blood levels Conclusion: Infrasensor transcutaneous measurement demonstrates similar results as that obtained from blood testing in the central laboratory.

Background: Growth differentiation factor‐15 (GDF‐15) is a novel biomarker of cardiac stress. GDF‐15 may be a stronger predictor of all‐cause death in patients with acute chest pain than traditional biomarkers such as high‐sensitivity troponin T and BNP (B‐type natriuretic peptide). However, data from US populations are lacking. Our objective was to determine whether GDF‐15 is an independent predictor of all‐cause death or acute myocardial infarction (AMI) at index visit, 30 days, and 90 days. Methods: We conducted a secondary analysis of the STOP‐CP (High Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification) trial, which prospectively enrolled adults (aged ≥21 years) from 8 US emergency departments with suspected AMI in 2017 to 2018. High‐sensitivity troponin T, BNP, and GDF‐15 assays were performed at a central laboratory on samples from baseline and 3 hours later. The primary outcome was the composite of all‐cause death or AMI at index visit, 30 days, and 90 days. Multiple logistic regression models assessed the association between GDF‐15 and all‐cause death or AMI at index visit, as well as at 30 and 90 days, while adjusting for age, sex, number of cardiac risk factors, ischemic ECG findings, high‐sensitivity troponin T, and N‐terminal pro‐B‐type natriuretic peptide. Results: We studied 1428 patients; median age was 58 (interquartile range, 49–66) years and 353 (25%) had a history of coronary artery disease. The composite outcome of all‐cause death or AMI occurred in 169 (12%) patients at index visit, an additional 21 (1.5%) at 30 days, and an additional 27 (1.9%) at 90 days. In multiple logistic regression models, GDF‐15 was independently associated with all‐cause death or AMI at 30 days (adjusted odds ratio per SD, 1.27 [95% CI, 1.06–1.54]) and 90 days (adjusted odds ratio R per SD, 1.55 [95% CI, 1.26–1.94]), but not during the index visit (adjusted odds ratio per SD, 1.00 [95% CI, 0.83–1.16]). Conclusions: Among adult emergency department patients with suspected AMI, GDF‐15 was independently associated with subsequent 30‐day and 90‐day all‐cause death or AMI. These data suggest a potential role for GDF‐15 in short‐term cardiac risk stratification in emergency department patients without AMI at index visit.

BACKGROUND: The High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) pathway risk stratifies emergency department patients with possible acute coronary syndrome. This study aims to determine if the High-STEACS hs-cTnT (high-sensitivity cardiac troponin T) pathway can achieve the ≥99% negative predictive value (NPV) safety threshold for 30-day cardiac death or myocardial infarction (CDMI) in a multisite US cohort of patients with and without known coronary artery disease (CAD). METHODS: A secondary analysis of the STOP-CP (High-Sensitivity Cardiac Troponin T [Gen 5 STAT Assay] to Optimize Chest Pain Risk Stratification) cohort, which enrolled adult emergency department patients with possible acute coronary syndrome at 8 US sites (January 25, 2017–September 6, 2018). Participants were classified into outpatient and admission dispositions using the High-STEACS hs-cTnT pathway. Known CAD was defined as prior MI, coronary revascularization, or ≥70% coronary stenosis. Outcomes included 30-day CDMI and efficacy, defined as the proportion identified for outpatient disposition. NPVs and negative likelihood ratios for 30-day CDMI were calculated. NPVs were compared between CAD subgroups using a Fisher exact test. RESULTS: Among 1351 patients, 53.2% (719/1351) were male, 31.4% (424/1351) had known CAD, and the mean age was 57.4±12.8 years. At 30 days, CDMI occurred in 13.8% (187/1351). High-STEACS classified 63.4% (857/1351) to outpatient disposition, of which 2.0% (17/857) had 30-day CDMI, corresponding to an NPV of 98.0% (95% CI, 96.8–98.8) and negative likelihood ratio of 0.13 (95% CI, 0.08–0.20). In patients with CAD, 46.9% (199/424) were classified to outpatient disposition, of which 4.0% (8/199) had 30-day CDMI. Among patients without CAD, 71.0% (658/927) were classified to outpatient disposition with 1.4% (9/658) having 30-day CDMI. The NPV for 30-day CDMI was 96.0% (95% CI, 92.2–98.2) in patients with CAD versus 98.6% (95% CI, 97.4–99.4) among patients without CAD ( P =0.04). The negative likelihood ratio for 30-day CDMI among patients with CAD was 0.16 (95% CI, 0.08–0.31) and 0.12 (95% CI, 0.06–0.22) among patients without CAD. CONCLUSIONS: The High-STEACS hs-cTnT pathway had high efficacy but was unable to achieve the ≥99% NPV safety threshold for 30-day CDMI. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02984436.

People with human immunodeficiency virus (HIV; PWH) smoke cigarettes at triple the rate of the general population in the United States. Efforts to increase quit rates in this group have met with limited success. The nicotine metabolite ratio (NMR) has shown promise as a phenotypic marker that may be useful in selecting the most appropriate cessation treatments for people who smoke cigarettes. We completed a randomized controlled trial of individual intensive counseling and/or varenicline treatment for PWH in the Baltimore area who smoke cigarettes, and we measured serum 3′ hydroxycotinine and cotinine at baseline and calculated the ratio of these two values, i.e., the NMR, for each participant. Herein, we present summary statistics and measures of association, or lack thereof, of NMR values with a variety of behavioral parameters and clinical outcomes related to tobacco use and tobacco treatment. The NMR was calculated for 155 PWH who were currently using tobacco cigarettes. The mean age was 52.9 years, 62.3% male, 91.0% Black, and they smoked a mean of 10.6 cigarettes/day. The mean NMR was 0.43, similar to that reported from other PWH cohorts. We did not find any significant correlation between NMR and cigarettes/day, nicotine dependence, temptation to smoke, or nicotine withdrawal symptoms. We did not find that lower NMR was predictive of successful cessation, nor was it associated with varenicline intolerance in those who received varenicline. Prevention Relevance: People with HIV suffer disproportionately from lung, head and neck, and other tobacco-related cancers as a consequence of high smoking rates. There is an urgent need to mitigate this harm, and the use of the NMR to personalize tobacco treatment is an area of active interest.

Background: Serum anti-Müllerian hormone (AMH) levels and antral follicle count are key in evaluating ovarian reserve (OR) for fertility. The performance of the Siemens Healthineers AMH assay was assessed on the ADVIA Centaur^® System. Methods: Analytical characteristics, clinical performance, and method comparison studies were performed in a prospective cohort of 532 women at fertility clinics. Serum AMH levels were determined using ADVIA Centaur, Beckman Access^®, and Roche Elecsys^® assays. Results: The limit of quantitation for the ADVIA Centaur AMH assay was 0.030 ng/mL. Repeatability was ≤2.9% CV, within-lab repeatability was ≤3.2% CV, and reproducibility was ≤4.4% CV. Results using serum or lithium heparin sample types were equivalent. Diagnostic sensitivity across assays ranged from 77.3% to 90.2% and specificity ranged from 51.0 to 71.0%; corresponding positive and negative predictive values ranged from 66.6% to 74.3% and 74.2% to 83.0%, respectively. Receiver operating characteristic analyses demonstrated that the assays have a high probability for discriminating between diminished–normal and high OR. ADVIA and Beckman assays agreed according to ADVIA = 1.00 × Beckman + 0.014 ng/mL, τ = 0.909, while a more modest correlation of ADVIA = 1.41 × Roche − 0.024 ng/mL, τ = 0.777 was observed with Roche assay. Conclusions: The ADVIA Centaur assay demonstrates acceptable analytical characteristics and clinical performance comparable to the Roche AMH assay and is essentially interchangeable with the Beckman AMH assay for reliable OR assessment.

Objective: Chest pain, a common emergency department presentation, requires rapid evaluation. The current gold standard of care is serial troponin measurements from blood draws along with an electrocardiogram and clinical presentation. However, an optical technology-based noninvasive wearable device, the Infrasensor, which can rapidly and transcutaneously assesses cardiac troponin I (cTnI), was recently developed. We aimed to perform a pilot study to evaluate the performance of the Infrasensor in cTnI defined cohorts.Methods: This was a 10-hospital prospective observational study in healthy US subjects with a normal cTnI level and in patients with an elevated local cTnI level. Healthy subjects as determined by a negative questionnaire and bloodwork underwent 3-minute Infrasensor measurement and levels of high-sensitivity cTnI (hs-cTnI), n-terminal pro-B-type natriuretic peptide (NTproBNP), creatinine, and glycosylated hemoglobin (HbA1c) were evaluated from blood. Patients with elevated cTnI had the same Infrasensor and blood sample measurements. Using a fivefold cross-validation technique, cTnI-based binary classification models that did and did not include age were trained on 80% and validated on 20% of the dataset (n=168; elevated hs-cTnI equally partitioned into five nearly equally-sized subsets ). Results: Of 840 patients, 727 (87.5%) had normal (nonelevated) cTnI levels while the remaining 113 had elevated cTnI. Median age was 61 years (interquartile range, 52–71 years) for the elevated cohort and 48 years (interquartile range, 32–57 years) for the nonelevated. Overall, 416 (50.5%) were female, with 33 of 113 (29.2%) in the elevated cohort and 383 of 727 (52.7%) in the nonelevated cohort. Overall, the sensitivity, specificity, negative and positive predictive values of the Infrasensor for identifying elevated cTnI were 0.90, 0.70, 0.98 and 0.48, respectively, with a C-statistic of 0.90 (95% confidence interval, 0.89–0.99).Conclusion: The Infrasensor accurately identifies elevated cTnI within 3 minutes of application.

BACKGROUND: Guidelines recommend antihypertensive medication for adults with both stage 1 hypertension (systolic blood pressure, 130–139 mm Hg or diastolic blood pressure, 80–89 mm Hg) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥10%. Cardiac biomarkers could facilitate a more targeted approach to the treatment of stage 1 hypertension. METHODS: We studied 1999 to 2004 National Health and Nutrition Examination Survey participants aged ≥20 years with untreated stage 1 hypertension without heart failure or ASCVD. We measured hs-cTnI (high-sensitivity cardiac troponin I), hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in stored serum. We used the Pooled Cohort Equations to predict 10-year ASCVD risk. All participants had linked mortality follow-up through December 31, 2019. RESULTS: Overall, 17.5% of US adults (32.2 million) had untreated stage 1 hypertension. Among these 32.2 million persons, 15.7% had ASCVD risk ≥10%, 5.6% had elevated hs-cTnI, 4.7% had elevated hs-cTnT, and 9.5% had elevated NT-proBNP. Among adults aged 65 to 79 years with untreated stage 1 hypertension, 80.5% had ASCVD risk ≥10%, 13.0% had elevated hs-cTnI, 15.2% had elevated hs-cTnT, and 29.4% had elevated NT-proBNP. Less than half of the adults aged ≥80 years with untreated stage 1 hypertension had elevated biomarkers. The cardiovascular disease mortality rates among all adults with untreated stage 1 hypertension and with either ASCVD risk ≥10%, elevated hs-cTnI, elevated hs-cTnT, or elevated NT-proBNP were 7.51, 7.74, 8.75, and 5.87 per 1000 person-years, respectively. CONCLUSIONS: Cardiac biomarkers may be more selective for informing risk-based treatment decisions in stage 1 hypertension, particularly among adults aged ≥65 years.

Background: Clinical decision-making for risk stratification for possible myocardial infarction (MI) uses high-sensitivity cardiac troponin (hs-cTn) thresholds that range from the limit of detection to several-fold higher than the upper reference limit (URL). To establish a minimum analytical variation standard, we can quantify the effect of variation on the population clinical measures of safety (sensitivity) and effectiveness [proportion below threshold, or positive predictive value (PPV)]. Methods: From large datasets of patients investigated for possible MI with the Abbott hs-cTnI and Roche hs-cTnT assays, we synthesized datasets of 1 000 000 simulated patients. Troponin concentrations were randomly varied several times based on absolute deviations of 0.5 to 3 ng/L and relative changes of 2% to 20% around the low-risk threshold (5 ng/L) and URLs, respectively. Results: For both assays at the low-risk thresholds, there were negligible differences in sensitivity (<0.3%) with increasing analytical variation. The proportion of patients characterized as low risk reduced by 30% to 29% (Roche) and 53% to 44% (Abbott). At the URL, increasing analytical variation also did not change sensitivity; the PPV fell by less than 3%. For risk stratification, increased delta thresholds (change between serial troponin concentrations) increased sensitivity at the cost of a decreased percentage of patients below the delta threshold, with the largest changes at the greatest analytical variation. Conclusions: At the low-risk threshold, analytical variation up to 3 ng/L minimally impacted the safety metric (sensitivity) but marginally reduced effectiveness. Similarly, at the URL even relative variation up to 25% minimally impacted safety metrics and effectiveness. Analytical variation for delta thresholds did not negatively impact sensitivity but decreased effectiveness.