Multi-center clinical evaluation of the Access AMH assay to determine AMH levels in reproductive age women during normal menstrual cycles.

BACKGROUND: AMH is widely used for assessing ovarian reserve, and it is particularly convenient, because it is thought to have minimal variability throughout the menstrual cycle. However, studies assessing the stability of AMH over the menstrual cycle have been conflicting. PURPOSE: The purpose of this study is to determine whether AMH levels vary across the normal menstrual cycle. DESIGN: A multi-center, prospective cohort study conducted at three US centers. METHODS: Fifty females with regular menstrual cycles aged 18-45 underwent serial venipuncture every 3-5 days starting in the early follicular phase and lasting up to 10 collections. AMH was tested using the Access 2 immunoassay system. RESULTS: Age-adjusted mixed-effect models utilizing data from 384 samples from 50 subjects demonstrated a within subject standard deviation of 0.81 (95% CI 0.75-0.88) with a coefficient of variation of 23.8% across the menstrual cycle and between subject standard deviation of 2.56 (95% CI 2.13-3.21) with a coefficient of variation of 75.1%. Intra-class correlation (ICC) of AMH across the menstrual cycle was 0.91. CONCLUSION: Overall, AMH levels, using the automated Access AMH assay, appear to be relatively stable across the menstrual cycle. Fluctuations, if any, appear to be small, and therefore, clinicians may advise patients to have AMH levels drawn at any time in the cycle.

Absolute and relative changes (delta) in troponin I for early diagnosis of myocardial infarction: Results of a prospective multicenter trial.

OBJECTIVES: We investigated absolute and relative cardiac troponin I (TnI) delta changes, optimal sampling protocols, and decision thresholds for early diagnosis of myocardial infarction (MI). Serial cardiac biomarker values demonstrating a rise and/or fall define MI diagnosis; however the magnitude of change, timing, and diagnostic accuracy of absolute versus relative (percentage) deltas remains unsettled. METHODS: We prospectively measured TnI (AccuTnI+3™, Beckman Coulter) at serial time intervals in 1929 subjects with chest pain or equivalent symptoms of acute coronary syndrome at 14 medical centers. Diagnosis was adjudicated by an independent central committee. RESULTS: Elevated TnI above a threshold of 0.03ng/mL demonstrated significant diagnostic efficacy (AUC 0.96). For patients with TnI<0.03ng/mL and symptom onset≥8h, 99.1% (NPV) were diagnosed with conditions other than MI. Absolute delta performed significantly better than relative delta at 1-3h (AUC 0.84 vs 0.69), 3-6h (0.85 vs 0.73), and 6-9h (0.91 vs 0.79). Current recommendations propose ≥20% delta within 3-6h; however, results were optimized using an absolute delta of 0.01 or 0.02ng/mL. Sensitivity results for absolute delta at 1-3h and 3-6h (75.8%, 78.3%) were superior to relative delta (48.0%, 61.3%). NPV (rule out) was 99.6% when baseline TnI<0.03ng/mL and absolute delta TnI<0.01ng/mL. CONCLUSIONS: Absolute delta performed significantly better than relative delta at all time intervals. Baseline TnI and absolute delta may be used in conjunction to estimate probability of MI. Consensus recommendations are supported for sampling on admission and 3h later, repeated at 6h in patients when clinical suspicion remains high.

Diagnostic performance of cardiac Troponin I for early rule-in and rule-out of acute myocardial infarction: Results of a prospective multicenter trial.

OBJECTIVES: To compare emergency department TnI serial sampling intervals, determine optimal diagnostic thresholds, and report representative diagnostic performance characteristics for early rule-in and rule-out of MI. METHODS: We prospectively measured TnI (AccuTnI+3™, Beckman Coulter) at serial time intervals in 1929 subjects with chest pain or equivalent ischemic symptoms suggestive of acute coronary syndromes at 14 medical centers. Diagnosis was adjudicated by an independent central committee. RESULTS: TnI ≥0.03ng/mL provided 96.0% sensitivity and 89.4% specificity at 1-3h after admission, and 94.9% sensitivity and 86.7% specificity at 3-6h. NPV (rule-out, non-MI) was 99.5% at 1-3h, and 99.0% at 3-6h when TnI is <0.03ng/mL. NPV was 99.1% when TnI is <0.03ng/mL and time of symptom onset is ≥8h. Approximately 50-58% (PPV) of patients with TnI ≥0.03ng/mL were diagnosed with MI, depending upon time from onset or admission; PPVs emphasize the importance of serial samples and delta TnI (rising or falling pattern) when low cutoffs are used. Nevertheless, even a single elevated TnI value increased the risk of MI. As TnI values rose, the probability of MI increased. Values ≥0.20ng/mL were associated with nearly 90% probability of MI. CONCLUSIONS: We report a large multicenter prospective adjudicated trial assessing troponin for early rule-in and rule-out using the Universal Definition of MI and conducted in primary care hospital-associated emergency departments. Our study demonstrates high diagnostic accuracy at early observation times, and reinforces consensus recommendations for sampling on admission and 3h later, repeated at 6h when clinical suspicion remains high.

Prospective evaluation of pregnancy-associated plasma protein-a and outcomes in patients with acute coronary syndromes.

OBJECTIVES: This study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). BACKGROUND: PAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality. METHODS: We measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 µIU/ml was chosen from pilot work in this cohort. RESULTS: PAPP-A >6.0 µIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 µg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine. CONCLUSIONS: PAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications.

Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index.

Anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the most prevalent forms of anemia and often occur concurrently. Standard tests of iron status used in differential diagnosis are affected by inflammation, hindering clinical interpretation. In contrast, soluble transferrin receptor (sTfR) indicates iron deficiency and is unaffected by inflammation. Objectives of this prospective multicenter clinical trial were to evaluate and compare the diagnostic accuracy of sTfR and the sTfR/log ferritin index (sTfR Index) for differential diagnosis using the automated Access(®) sTfR assay (Beckman Coulter) and sTfR Index. We consecutively enrolled 145 anemic patients with common disorders associated with IDA and ACD. Subjects with IDA or ACD + IDA had significantly higher sTfR and sTfR Index values than subjects with ACD (P < 0.0001). ROC curves produced the following cutoffs for sTfR: 21 nmol/L (or 1.55 mg/L), and the sTfR Index: 14 (using nmol/L) (or 1.03 using mg/L). The sTfR Index was superior to sTfR (AUC 0.87 vs. 0.74, P < 0.0001). Use of all three parameters in combination more than doubled the detection of IDA, from 41% (ferritin alone) to 92% (ferritin, sTfR, sTfR Index). Use of sTfR and the sTfR Index improves detection of IDA, particularly in situations where routine markers provide equivocal results. Findings demonstrate a significant advantage in the simultaneous determination of ferritin, sTfR and sTfR Index. Obtaining a ferritin level alone may delay diagnosis of combined IDA and ACD.