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Circulation 02/2012; 125(6):e358; author reply e359. · 14.74 Impact Factor
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Clinical Chemistry 10/2010; 56(12):1902-4. · 7.91 Impact Factor
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ABSTRACT: Document patient choices and screening performance (false positive and detection rates) when three improved Down syndrome screening protocols were introduced coincidentally.
Second-trimester 'triple marker' screening was expanded by adding second-trimester dimeric inhibin-A (four-marker), with or without first-trimester pregnancy-associated plasma protein-A (five-marker). Nuchal translucency (NT) measurements were included when available from accredited sonographers (six-marker). For assigning risk, two sets of marker distribution parameters were evaluated.
Over 3.5 years, 8571 women enrolled (median age 30.6 years). Uptake of the four-, five- and six-marker protocols was 18%, 46% and 36%, respectively. Of those selecting an integrated test (five or six markers), 9.7% did not provide the second trimester serum sample. False positive rates decreased with added markers (5.2%, 5.1% and 2.5%, respectively) and varied between the two parameter sets, while detection remained high. Overall, 21 of 23 cases were detected (91%, 95% CI 73-98%) at a 4.2% false positive rate (95% CI 3.3-5.1%).
Integrated screening protocols were chosen 4.6 times more often than four-marker screening (82% vs. 18% uptake). Overall detection was higher and false positives lower, consistent with recent guidelines. Important performance factors include gestational dating method, risk cut-off, and the parameter set used to assign risk.
Prenatal Diagnosis 05/2010; 30(5):459-66. · 2.11 Impact Factor
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Clinical Chemistry 03/2010; 56(3):487-9. · 7.91 Impact Factor
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ABSTRACT: Within the past decade, the use of biomarkers to detect myocardial injury in the emergency department (ED) has been given increasing prominence as evident by the numerous studies and guidelines documenting their use. This review details the scope of the clinical problem, the history of changes in the definition of myocardial infarction (MI) and the new approaches, as well as suggestions for using laboratory biomarkers in the early detection of MI in the ED.
Clinical biochemistry 12/2009; 43(6):539-44. · 2.02 Impact Factor
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ABSTRACT: To determine if a cytokine panel could be informative regarding subsequent heart failure(HF)/death.
In 216 subjects presenting with chest pain to an emergency department in 1996, EDTA plasma (-70 degrees C) was thawed for IL-6, MCP-1, IL-10, VEGF, EGF measurement.
Subjects with any three cytokines elevated were at higher risk for HF/death compared to those with < or = two cytokines elevated.
A cytokine panel might be useful for risk stratification for HF/death.
Clinical biochemistry 11/2009; 43(4-5):505-7. · 2.02 Impact Factor
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ABSTRACT: The next-generation, high-sensitivity cardiac troponin assays can measure quantifiable concentrations of cTn in a majority of individuals, but there are few studies assessing these assays for risk stratification. The present study was undertaken to determine if a research hs-cTnI assay can be useful for predicting death/myocardial infarction (MI), both short- and long-term, in an emergency department acute coronary syndrome (ACS) population.
In a cohort of 383 subjects, originally recruited in 1996, presenting to the emergency department with symptoms suggestive of ACS, the heparin plasma obtained at initial presentation was thawed and measured in 2007 with a research hs-cTnI assay. AccuTnI (Beckman Coulter) measurements were made on these same samples in 2003. The population was divided into 4 groups by hs-cTnI: <5.00, 5.00-9.99, 10.00-40.00, and >40.00 ng/L. Kaplan-Meier, Cox proportional hazards, ROC curves, and logistic regression analyses were used to identify which hs-cTnI concentrations were predictive of death/MI within 10 years after presentation.
There were significant differences between the hs-cTnI groups for the probability of death/MI up to 10 years after presentation (P < 0.05). At 6 months, patients with hs-cTnI > or =10.00 ng/L were at higher risk for death/MI (hazard ratio >3.7; P < 0.05) compared with those having hs-cTnI <5.00 ng/L. ROC curve analysis for death/MI at 30 days with the hs-cTnI assay had an area under the curve of 0.74 (95% CI 0.65-0.82), with logistic models yielding an optimal assay threshold of 12.68 ng/L.
This research hs-cTnI assay appears useful for risk stratification for death/MI in an ACS population.
Clinical Chemistry 09/2009; 55(10):1809-15. · 7.91 Impact Factor
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Clinica chimica acta; international journal of clinical chemistry 08/2009; 408(1-2):139-40. · 2.54 Impact Factor
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ABSTRACT: Long-term risk stratification in patients presenting with acute coronary syndromes (ACS) is possible by measuring cardiac troponin (cTn). The present study examined whether PAPP-A measured in an emergency department (ED) chest pain population in association with conventional and novel high sensitivity cTn (hs-cTnI) assays can predict long-term mortality.
In 320 patients with cTn measurements the earliest heparinized plasma PAPP-A concentration after presentation was used for risk stratification for death by Kaplan-Meier and Cox analyses. Subgroup analyses using the earliest PAPP-A concentrations were also performed in a cohort of subjects with presentation cTnI < or = 99th percentile but with significantly changing cardiac troponin concentrations as measured by the AccuTnI assay and the hs-cTnI assay (n=45 and 120 subjects, respectively).
Subjects with PAPP-A concentrations in the highest tertile were at higher risk for death (HR > 2.00; p < or = 0.05 at 2 years) even after adjusting for cTnI at presentation. In the cohort with cTnI < or = 99th percentile but with changing hs-cTnI concentrations, subjects in the top PAPP-A tertile had a higher probability for death (p=0.02).
Early measurement of PAPP-A may identify chest pain patients at higher risk for long-term death. Additional prospective ACS studies are required to fully elucidate PAPP-A's role.
Clinical biochemistry 04/2009; 42(10-11):1012-8. · 2.02 Impact Factor
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ABSTRACT: Improvements in cardiac troponin (cTn) assays have increased the rapidity with which clinicians can identify patients with changing cTn concentrations (rise or fall) indicative of acute myocardial injury. The aim of the present study was to characterize a new, high-sensitivity cTnI (hs-cTnI) assay and examine whether increased sensitivity can result in still earlier detection of evolving injury.
We determined the limit of detection, precision profiles, and preliminary estimates of the 99th percentile for the Beckman Coulter hs-cTnI assay in 125 healthy individuals (age <55 years, 54% male). We compared AccuTnI and hs-cTnI to assess whether change criteria for early concentration changes (i.e., > or =3SD for low concentrations and 20% difference for concentrations >0.10 microg/L) were exceeded in the first 2 specimens (median time between specimens, 1 h; 25th-75th percentile, 1-3 h) from subjects with symptoms suggestive of cardiac ischemia (n = 290).
The limit of detection for the hs-cTnI assay was 2.06 ng/L, and the 20% CV and 10% CV concentrations were 2.95 and 8.66 ng/L, respectively. The preliminary 99th percentile estimates in lithium heparin, serum, and EDTA plasma were 9.20, 8.00, and 8.60 ng/L, respectively. In 108 patients with myocardial injury based on the peak AccuTnI concentration, applying the change criteria on the 2 earliest specimens identified 81% (95% CI 73%-88%) of patients using the hs-cTnI assay compared to 62% (53%-71%) using the AccuTnI assay (P < 0.001).
Although more extensive validation studies are required, this Beckman Coulter hs-cTnI assay appears to detect patients with evolving myocardial injury earlier.
Clinical Chemistry 01/2009; 55(3):573-7. · 7.91 Impact Factor
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ABSTRACT: To determine if elevations of adhesion molecules in acute coronary syndrome (ACS) are useful for risk stratification.
A cell adhesion array (Randox Ltd.) and NT-proBNP were measured in 216 ACS patients.
Kaplan-Meier and Cox models indicate early elevations of NT-proBNP but not the adhesion molecules are predictive of future death/myocardial infarction.
Elevations of adhesion molecules early after pain onset in ACS are not useful for long-term risk stratification.
Clinical Biochemistry 05/2008; 41(6):436-9. · 2.08 Impact Factor
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ABSTRACT: Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations.
We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2-4 hours, and a later second specimen obtained at 9 hours, IQR 9-9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI >0.04 ug/L; cTnT >0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained >8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) > or =1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years.
In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P <0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P = 0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P > or =0.15).
A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.
Clinical Chemistry 05/2008; 54(4):747-51. · 7.91 Impact Factor
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ABSTRACT: For patients presenting with acute coronary syndrome (ACS) to the emergency department, early identification of those that are at high risk for subsequent myocardial necrosis or adverse outcomes would allow earlier or more aggressive treatment. We determined if a panel of biomarkers can be used to identify high risk patients.
A cohort (84 females/132 males) from our 1996 ACS study population that had EDTA specimens stored (-70 degrees C) was selected and the earliest available specimen was analyzed for 11 biomarkers (IL-6, IL-8, MCP-1, VEGF, L-selectin, P-selectin, E-selectin, ICAM-1, VCAM-1, NT-proBNP, cTnT). These data were linked to the existing cTnI and health outcome databases for this population. ROC curve analysis for myocardial necrosis (i.e., peak cTnI >0.04 microg/l) identified 3 candidate biomarkers. These 3 biomarkers were applied together to generate a panel test (2 of the 3 biomarkers increased for a positive result) and assessed for its ability to identify patients at risk for myocardial necrosis and the combined endpoint of death, myocardial infarction (MI) and heart failure (HF).
The panel test (IL-6, NT-proBNP, E-selectin) alone detected 60% (95% CI: 49-69; false positive rate: 26%) of subjects that would be classified with myocardial necrosis. Kaplan-Meier and Cox proportional analyses indicated that patients positive by the biomarker panel (including those with cTnI < or =0.04 microg/l) had significantly worse outcomes (death/MI/HF) as compared to those negative by both cTnI and the panel test.
A biomarker panel analyzed early after pain onset can identify individuals at risk for both myocardial necrosis and the combined endpoint of death/MI/HF. Additional prospective studies are required to assess this panel for both early MI detection and to further refine which health outcomes (death, MI, HF) are associated with positive panel results.
Clinica Chimica Acta 02/2008; 387(1-2):133-8. · 2.54 Impact Factor
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ABSTRACT: Inflammation in acute coronary syndrome (ACS) can identify those at greater long-term risks for heart failure (HF) and death. The present study assessed the performance of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) (cytokines involved in the activation and recruitment of leukocytes) in addition to known biomarkers [e.g., N-terminal pro-brain natriuretic peptide (NT-proBNP)] for predicting HF and death in an ACS population.
In a cohort of 216 ACS patients, NT-proBNP (Elecsys; Roche) and IL-6, IL-8, and MCP-1 (evidence investigator; Randox) were measured in serial specimens collected early after symptom onset (n = 723). We collected at least 2 specimens from each participant: an early specimen (median 2 h; interquartile range 2-4 h) and a later specimen (9 h; 9-9 h), and used the later specimens' biomarker concentrations for risk stratification.
An increase in both IL-6 and NT-proBNP was observed but not for IL-8 or MCP-1 early after pain onset. Kaplan-Meier analysis demonstrated that individuals with increased NT-proBNP (>183 ng/L) or cytokines (IL-6 > 6.4 ng/L; above upper limit of normal for IL-8 or MCP-1) had a greater probability of death or HF in the following 8 years (P <0.05). In a Cox proportional hazard model adjusted for both CRP and troponin I, increased IL-6, MCP-1, and NT-proBNP remained significant risk factors. Combining all 3 biomarkers resulted in a higher likelihood ratio for death or HF than models restricted to any 2 of these biomarkers.
IL-6, MCP-1, and NT-proBNP are independent predictors of long-term risk of death or HF, highlighting the importance of identifying leukocyte activation and recruitment in ACS patients.
Clinical Chemistry 12/2007; 53(12):2112-8. · 7.91 Impact Factor
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Clinica Chimica Acta 06/2007; 380(1-2):245-6. · 2.54 Impact Factor
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ABSTRACT: The 2003 American Heart Association (AHA) definition for myocardial infarction (MI) requires an "adequate set" (i.e. at least 6 h between measurements) of biomarkers and specifically troponin for the diagnosis of MI. The aim of the present study was to assess the performance of myoglobin, the CKMB isoforms, and cardiac troponin I (cTnI) in specimens earlier than the requisite 6 h after presentation, in a population originally characterized using World Health Organization (WHO) criteria.
In 1996, 228 acute coronary syndrome patients with an "adequate sample set" had their specimens assayed for CKMB isoforms and myoglobin. In 2003, the same specimens were analyzed with the AccuTnI troponin I assay and myoglobin (Beckman Coulter Access immunoassay).
The clinical sensitivities for both myoglobin and the CKMB isoforms were >90% when the population was classified by WHO criteria. However the sensitivities were <70% when the ESC/ACC MI definition was used. Analyzing cTnI at earlier time points as long as there was at least 3 h between specimens or at least 1 specimen 6 h from pain onset did not misclassify subjects based on adverse outcomes in the year following their presentation.
Contemporary assays for cTnI with increased analytical sensitivity reduce the utility of myoglobin and CKMB isoforms to rule-out an AMI.
Clinica Chimica Acta 05/2007; 380(1-2):213-6. · 2.54 Impact Factor
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ABSTRACT: To assess the ability of C-reactive protein (CRP) to predict long-term outcomes in a chest pain population.
CRP was measured at presentation in 446 emergency department patients with acute coronary syndromes. All-cause mortality and hospital discharges for acute myocardial infarction (AMI) and congestive heart failure (CHF) were obtained for up to 8 years following the event.
Kaplan-Meier analyses indicated that patients with CRP concentrations above the American Heart Association scientific statement cut-off had a higher rate for death and CHF admissions. After adjusting for troponin concentrations, in a Cox proportional hazard model, only CRP concentrations indicative of an acute phase response (i.e., >7.44 mg/L) were associated with a significant risk for death after 5 years and CHF readmission after 2 years.
Patients presenting early with chest pain with elevated CRP concentrations have a greater long-term risk for death and heart failure.
Clinical Biochemistry 04/2007; 40(5-6):326-9. · 2.08 Impact Factor
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ABSTRACT: Recent data suggest that older men with detectable cardiac troponin I (cTnI) concentrations that remain below the 99th percentile concentration cutoff are at increased risk for subsequent cardiovascular events. We designed this study to extend this observation by examining risk prediction in both men and women presenting to an emergency department with chest discomfort.
We obtained data for all-cause mortality and hospital discharges associated with either acute myocardial infarction (AMI) or congestive heart failure (CHF) for up to 8 years after the initial presentation in 448 patients who originally presented in 1996 with acute coronary syndrome (ACS). We performed retrospective analysis for cTnI (AccuTnI; Beckman Coulter) in frozen plasma samples based on the patients' reported time from onset of symptoms. Peak cTnI concentration was used for risk assessment.
Patients with cTnI concentrations > or =0.02 microg/L (i.e., limit of detection), including those whose peak values remained below the 99th percentile (0.04 microg/L), were at greater risk for death and AMI/CHF readmissions at 2, 5, and 8 years of follow-up compared with those with peak cTnI <0.02 microg/L. All results were statistically significant (P <0.05) except for death within 2 years among patients with normal but detectable cTnI (0.02 to 0.03 microg/L), relative to the group with values <0.02 microg/L. Kaplan-Meier analyses indicated that both men and women with cTnI > or =0.02 microg/L had worse outcomes (P <0.001).
Both men and women who present with possible ACS with detectable cTnI concentrations that remain below the 99th percentile are at a greater risk for future adverse events.
Clinical Chemistry 03/2007; 53(2):220-7. · 7.91 Impact Factor
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ABSTRACT: In a population originally classified for acute myocardial infarction (AMI) by the World Health Organization (WHO) definition, we compared the health outcomes after retrospectively reclassifying with the European Society of Cardiology and the American College of Cardiology (ESC/ACC) AMI definition, using the peak cardiac troponin I (cTnI) concentrations. The health outcomes were based on the WHO definition and occurred in an era that preceded the use of cardiac troponin biomarkers.
For 448 patients who presented to the emergency department with symptoms suggestive of cardiac ischemia in 1996, we obtained data for all-cause mortality and recurrent AMI for up to 1 year after the initial presentation. We performed retrospective analysis of the patients' frozen plasma samples to measure cTnI (AccuTnI, Beckman Coulter).
At 30, 120, and 360 days, the risk for AMI/death in patients positive for AMI by only the ESC/ACC criteria was significantly lower than the risk in patients positive by both ESC/ACC and WHO criteria, and significantly higher than in patients negative according to both criteria. In a separate analysis, patients with a peak cTnI>0.10 microg/L were at greater risk for AMI/death than patients with cTnI concentrations of 0.04-0.10 microg/L. Patients negative by both definitions or with peak cTnI concentrations<0.04 microg/L had the highest event-free survival rates (92% and 94%, respectively) at 1 year.
In a troponin-naïve population, patients classified as positive for AMI by only the ESC/ACC criteria have a prognosis that appears to be intermediate between those classified positive by both the WHO and ESC/ACC definitions and those who meet neither criteria.
Clinical Chemistry 12/2006; 52(11):2028-35. · 7.91 Impact Factor
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Wendy Y Craig,
James E Haddow,
Glenn E Palomaki,
Richard I Kelley,
Lisa E Kratz,
Cedric H L Shackleton,
Josep Marcos,
G Stephen Tint, Andrew R MacRae,
Malgorzata J Nowaczyk,
Edward M Kloza,
Mira B Irons,
Marie Roberson
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ABSTRACT: Smith-Lemli-Opitz syndrome (SLOS) is a rare hereditary disorder of cholesterol metabolism. We examine the feasibility of identifying SLOS as a part of a routine prenatal screening and evaluate diagnostic testing in maternal urine (or serum), in addition to amniotic fluid.
Our SLOS risk algorithm utilized three Down syndrome screening markers (estimated 62% detection rate; 0.3% screen-positive rate). Fifteen North American prenatal screening programs implemented this algorithm.
SLOS risk was assigned to 1 079 301 pregnancies; 3083 were screen-positive (0.29%). Explanations were found for 1174, including 914 existing fetal deaths. Among the remaining pregnancies, 739 were screen-positive only for SLOS; 1170 were also screen-positive for other fetal disorders. Five of six SLOS pregnancies (83%) were screen-positive. All six had sonographic findings, were biochemically confirmed, and were terminated. Maternal urine steroid measurements were confirmatory in four cases tested. Second-trimester prevalence among Caucasians was 1 in 101 000 (1 in 130 000 overall; no cases in other racial groups). Among 739 pregnancies screen-positive only for SLOS, two cases were identified; another 69 had major fetal abnormalities.
Although SLOS occurred less often than previously reported, many other major abnormalities were detected. Implementing the algorithm as an adjunct to Down syndrome screening may be feasible.
Prenatal Diagnosis 10/2006; 26(9):842-9. · 2.11 Impact Factor
