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European Journal of Heart Failure 2004 6(3):301-308; doi:10.1016/j.ejheart.2003.12.013
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© 2004 European Society of Cardiology

N-terminal probrain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnoea and ventricular dysfunction*

Antoni Bayés-Genísa,e,*, Miquel Santaló-Belb, Edgar Zapico-Muñizc, Laura Lópeza, Carlos Cotesa, Jesús Bellidod, Rubén Letaa, Pere Casand and Jordi Ordóñez-Llanosc,f

a Cardiology Department, Hospital de la Santa Creu i Sant Pau C/Sant Antoni Ma Claret 167, 08025 Barcelona, Spain
b Emergency Department, Hospital de la Santa Creu i Sant Pau Barcelona, Spain
c Biochemistry Department, Hospital de la Santa Creu i Sant Pau Barcelona, Spain
d Pneumology Department, Hospital de la Santa Creu i Sant Pau Barcelona, Spain
e Department of Medicine, Universitat Autònoma Barcelona, Spain, Barcelona, Spain
f Department of Biochemistry and Molecular Biology Universitat Autònoma, Barcelona, Spain

* Corresponding author. Tel.: +34-93-556-92-58; Fax: +34-93-291-94-24 E-mail address: abayesgenis{at}hsp.santpau.es


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: To evaluate the utility of NT-proBNP in the emergency diagnosis and in-hospital monitoring of patients with acute dyspnoea and ventricular dysfunction.

Background: Misdiagnosis of heart failure (HF) is common in the urgent care setting using clinical diagnostic tests. Reports show that BNP is useful to diagnose HF in patients with acute dyspnoea.

Methods: Prospective study of 100 patients attending the Emergency Department (ED) for acute dyspnoea. Final diagnosis was determined on the basis of ED data sheets, echocardiography and pulmonary function tests. NT-proBNP levels were obtained on admission, at 24 h and at day 7.

Results: Patients with ventricular dysfunction were sub-classified into decompensated HF and masked HF, defined as HF with concomitant signs of pulmonary disease. Decompensated and masked HF patients had significantly higher NT-proBNP values than patients with non-cardiac dyspnoea (normal ventricular function) (920±140 and 978±363 vs. 50±15 pmol/L; P<0.001 and P<0.01, respectively). The mean area under the ROC curve for NT-proBNP was 0.957 (95% CI, 0.918 to 0.996, P<0.001). In multiple logistic-regression analysis NT-proBNP>115 pmol/l was the strongest independent predictor of ventricular dysfunction (odds ratio 45.4; 95% CI: 4.5–452.3). At day 7, a significant and similar reduction in NT-proBNP was observed in the two groups of patients with ventricular dysfunction (P<0.001 vs. admission values), but complete clinical resolution was less frequent in masked HF patients (P<0.05 vs. decompensated HF).

Conclusions: NT-proBNP is a new candidate marker for the detection and exclusion of ventricular dysfunction in patients attending the ED for acute dyspnoea. NT-proBNP may also serve to monitor outcome during hospitalization.

Key Words: Abbreviations • BNP, Brain natriuretic peptide • NT-proBNP, N-terminal probrain natriuretic peptide • NYHA, New York Heart Association • ECG, Electrocardiogram • LVEDD, Left ventricle end diastolic diameter • LVEF, Left ventricular ejection fraction • LV, Left ventricle • RV, Right ventricle

Received October 20, 2003; Accepted December 18, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure is an increasingly common disorder, with an age-adjusted prevalence in the population ranging between 1.5 and 3.5% [1]. Heart failure, characterized by a poor prognosis and quality of life [2,3] is the leading cause of hospitalization in adults over 65, and is currently the most costly cardiovascular disorder in western countries, with estimated annual expenditure in the United States in excess of $20 billion [4].

Heart failure is a clinical syndrome in which structural or functional alterations of the heart lead to secondary phenomena such as exertional dyspnoea and circulatory congestion [5]. Current diagnosis of heart failure is based on medical history and physical examination and further confirmed by other tests, mainly echocardiography [5]. Nevertheless, clinical misdiagnosis in the Emergency Department (ED) is common: 25 to 50% of patients presenting with decompensated heart failure are initially misdiagnosed [6], and echocardiography is not always available in urgent care settings [7]. Thus, new diagnostic tests are required to confirm ventricular dysfunction in cases where the diagnosis is not clear, such as lung or systemic diseases with breathlessness, or in patients with coexisting heart and lung diseases. Early and accurate diagnosis of ventricular dysfunction in the ED may permit the prompt onset of intensive therapy and subsequently reduce health costs.

Measurement of natriuretic peptides has been proposed for the screening of ventricular dysfunction [8]. Natriuretic peptides are produced within the heart and released into the circulation in response to increased wall tension, reflecting increased volume or pressure overload [9]. Under pathologic stimuli, the prohormone of BNP is synthesized, cleaved to BNP, the biologically-active peptide, releasing NT-proBNP, a 76aa amino terminal peptide with no known biological function [6]. NT-proBNP concentrations are very stable in blood and circulating levels are higher than those of BNP, since the N-terminal fragment is not cleared by cell receptors [6]. Both peptides have proved equally useful for the diagnosis of ambulatory patients with heart failure and left ventricular dysfunction [10–12], and BNP has already been tested in the ED for the diagnosis of heart failure [13].

The objective of the present study was to determine the utility of NT-proBNP for the diagnosis of ventricular dysfunction in patients attending the ED for acute dyspnoea, and evaluate the changes in NT-proBNP concentrations after intensive treatment initiated during admission.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
Patients aged 40–88 years with symptoms of acute dyspnoea were consecutively recruited in the ED of a single university hospital. Eligibility included shortness of breath at rest as the most prominent complaint. Exclusion criteria included NYHA classes I and II, age under 40, dyspnoea secondary to chest trauma or cardiac tamponade, and acute coronary syndromes unless the predominant presentation was heart failure. Furthermore, patients with severe renal insufficiency and liver cirrhosis were also excluded to avoid possible effects on NT-proBNP values. The study was approved by our Institutional Review Board.

Once the patient was identified as having dyspnoea, written informed consent was obtained and a blood sample collected for NT-proBNP measurement. For each patient enrolled in the study, physicians assigned to the ED collected information from medical history, physical examination, results of other blood tests, chest X-rays and ECGs to assess the probability of the patient having heart failure. ED physicians were blinded to the results of NT-proBNP measurements and patients were classified as having a high or low probability of heart failure, or as clinically ‘doubtful’ for a cardiac or respiratory diagnosis of their dyspnoea.

All patients included in the study were hospitalized and treated according to institutional guidelines. Additional blood samples collected into glass, evacuated tubes without anticoagulants (Vacutainer® Beckton Dickinson, Orange, NJ, USA) were obtained at 24 h and 7 days after admission to monitor the effect of medical therapy on NT-proBNP concentrations.

2.2. Confirmation of the diagnosis
To determine patients’ actual diagnosis, two cardiologists blinded to NT-proBNP concentrations and the ED diagnosis reviewed all medical records pertaining to the patients and classified them as follows: those with ventricular dysfunction (LV or RV dysfunction) and those with normal ventricular function and non-cardiac dyspnoea. Patients with ventricular dysfunction were sub-classified into decompensated heart failure and masked heart failure. Masked heart failure was defined as heart failure clinically difficult to diagnose owing to the presence of pulmonary disease which produced overlapping signs and symptoms.

The final diagnosis was established on the basis of ED data sheets and additional information that became available during hospitalization. This information included results of an echocardiogram, spirometry, pulmonary volumes and arterial blood gases performed within 7 days after admission to the ED. Left ventricular dilatation (LVEDD>55 mm) and LVEF below 45% identified patients with systolic LV dysfunction; left ventricular hypertrophy and LVEF above 45%, with inversion or pseudonormalization of E/A ratio identified diastolic LV dysfunction. In presence of preserved LV function and atrial fibrillation, an E/E' ratio >15 was used to identify patients with increased mean left ventricular diastolic pressure [14]. Dilatation of right sided cavities with hypokinesis of RV free wall identified RV dysfunction.

According to the clinical course during hospitalization, patients were assessed at day 7 as either complete resolution of the acute event, stabilization of signs and symptoms to chronic status or persistent decompensated heart failure. Complete resolution of the acute event meant return to NYHA I and was most often seen in cases in which the cause of decompensation was an arrhythmia.

2.3. Cardiac marker assays
Blood samples were obtained on admission, at 24 h and 7 days after admission. Serum was separated by centrifugation at 1500xg and stored at –80 °C until analysis; all samples from the same patient were analyzed in the same batch. NT-proBNP (in pmol/l) and cardiac troponin T (cTnT, in µg/l) were measured by the commercially available electrochemiluminescence immunoassay on an Elecsys 1010 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The intra-assay coefficient of variation for NT-proBNP was 1.8% for 26 pmol/l and 3.1% for 500 pmol/l; the inter-assay coefficient of variation was 5.5% for 22 pmol/l, 7.0% for 367 pmol/l and 7.3% for 1456 pmol/l. To convert pmol/l to pg/ml, multiply pmol/l by 8.457. cTnT was considered positive for myocardial damage when over 0.04 µg/l (the value measured in our laboratory with 10% analytical imprecision).

To establish our NT-proBNP reference values, we selected a control group of 86 subjects over 40 years of age (57±15 years; 40% women) without dyspnoea, no known cardiovascular risk factors and no clinical evidence of heart or lung disease. All gave their informed consent. A basal blood sample was drawn under the same conditions as for the patients.

2.4. Statistical analysis
Descriptive statistics include mean±S.E.M. The Kruskal–Wallis test was used to compare more than two non-paired groups; between groups comparisons of variables were performed using the Mann–Whitney's U test for unpaired and the Wilcoxon signed rank test for paired groups, respectively. Associations among circulating levels of NT-proBNP and cTnT were assessed by Spearman's rank correlation coefficient. Receiver-operating-characteristic (ROC) analysis was performed for NT-proBNP levels. We used a multivariate stepwise logistic regression analysis to estimate adjusted odds ratios for the risk of ventricular dysfunction in the study population. Relevant odds ratios included the 95% confidence intervals (CI). A P value ≤0.05 was considered statistically significant. Raw data were analyzed by an independent statistician.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Study population
Between April 2002 and February 2003, 100 patients attending our ED with symptoms of dyspnoea were consecutively enrolled. Six patients died during hospital admission before a confirmatory diagnosis based on echocardiography and pulmonary function tests became available. Five patients withdrew from the study. Final cardiology assessment of the remaining 89 patients revealed that 52 (58.4%) had decompensated heart failure as the main cause of dyspnoea, 22 (24.7%) had masked heart failure and 15 (16.9%) had normal ventricular function. The main clinical characteristics of the study patients are shown in Table 1.


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  		Table 1 Demographics, medical history and physical examination

 
The initial diagnosis was wrong in 18 patients (20.2%): heart failure was wrongly diagnosed in one patient (1.1%) and missed in 17 patients (19.1%) (six had decompensated and 11 masked heart failure). In addition, 14 patients (15.7%) had a doubtful initial diagnosis; two of these patients had a final diagnosis of decompensated heart failure, nine masked heart failure and three non-cardiac dyspnoea.

3.2. NT-proBNP concentrations on admission
3.2.1. According to final diagnosis
Fig. 1 presents a box plot of NT-proBNP values for the three groups of patients and controls. Patients with ventricular dysfunction, both decompensated and masked heart failure, had significantly higher NT-proBNP values than patients with normal ventricular function and non-cardiac dyspnoea (P<0.001 and P<0.01, respectively). NT-proBNP values on admission were not significantly different between the two groups of patients with ventricular dysfunction: those with decompensated heart failure (920±140 pmol/l) and those with masked heart failure (978±363 pmol/l). Patients with non-cardiac dyspnoea and normal ventricular function had NT-proBNP concentrations of 50±15 pmol/l (Table 2). In our reference group, mean concentrations were of 9±3 pmol/l, being significantly lower than those of patients with acute dyspnoea of non-cardiac (P<0.05) and cardiac origin (P<0.001 for both groups with ventricular dysfunction).


Figure 1
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  		Fig. 1 Box plots showing NT-proBNP concentrations (in logarithm) of patients attending the ED with dyspnoea and controls (see Section 2). Boxes show median and interquartile ranges; bars represent highest and lowest values. NT-proBNP values are expressed in pmol/l. To convert pmol/l to pg/ml, multiply pmol/l by 8.457.

 


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  		Table 2 NT-proBNP levels (mean±S.D.; pmol/l) on admission, at 24 h and at 7 days

 
3.2.2. According to echocardiography
Echocardiographic analysis of patients with ventricular dysfunction identified 33 patients who met the criteria for systolic LV dysfunction, 28 with diastolic LV dysfunction, seven patients with significant valvular heart disease and six patients with RV dysfunction. No significant differences in NT-proBNP concentrations were observed according to echocardiographic diagnosis, although a trend towards higher NT-proBNP values was found in patients with systolic LV dysfunction compared to those with diastolic LV dysfunction (1118±199 pmol/l vs. 848±297 pmol/l, respectively; P=0.054).

3.2.3. According to troponin T concentration
Cardiac troponin T levels >0.04 µg/l were found in 27% of patients with decompensated heart failure, in 35% of those with masked heart failure, and in none of the patients with normal ventricular function. NT-proBNP levels were significantly higher in patients with ventricular dysfunction who had positive troponin T than those with negative troponin T (1753±403 pmol/l vs. 507±85 pmol/l, respectively; P<0.001). Spearman's rank correlation showed a positive association between cTnT and NT-proBNP levels (R=0.6, P<0.0001).

3.2.4. NT-proBNP as predictor of ventricular dysfunction
NT-proBNP concentration was the single most accurate predictor of the presence or absence of ventricular dysfunction. The capacity of NT-proBNP to identify structural heart disease in patients with acute dyspnoea was assessed with a ROC analysis (Fig. 2). The mean area under the ROC curve for NT-proBNP was 0.957 (95% CI, 0.918–0.996, P<0.001), thus suggesting that NT-proBNP is a valuable marker for the identification of patients with dyspnoea of cardiac origin. An NT-proBNP cutoff value of 115 pmol/l had specificity of 93%, sensitivity of 90% and accuracy of 91.8% to identify patients with dyspnoea of cardiac origin from other causes of dyspnoea. Lower NT-proBNP concentrations were associated with more accurate negative predictive values; for an NT-proBNP value of 30 pmol/l, the negative predictive value in our series was 100%. Fourteen percent of our patients presented values under 30 pmol/l, 77% above 115 pmol/l and 9% between both cut-off points, respectively. Interestingly, in our control cohort the 95th percentile was 31 pmol/l, almost superimposed to the rule-out cutoff value proposed.


Figure 2
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  		Fig. 2 ROC curve for various cutoff NT-proBNP values in differentiating patients with dyspnoea of cardiac origin. A cutoff value of 115 pmol/l (973 pg/ml) appeared useful to rule-in dyspnoea of cardiac origin, and a cutoff value of 30 pmol/l (254 pg/ml) appeared useful to rule-out the cardiac origin of the dyspnoea.

 
In multiple logistic regression analysis, we observed that the addition of NT-proBNP increased the combined power of the history, symptoms, signs, X-ray studies and laboratory findings. The model showed that cephalization of vessels on chest X-ray was the only clinical independent predictor of ventricular dysfunction (odds ratio 10.3; 95% CI: 0.9–113.8). A value of NT-proBNP ≥115 pmol/l was the strongest independent predictor of ventricular dysfunction, with an odds ratio of 45.4 (95% CI: 4.5–452.3).

To assess the utility of NT-proBNP in non-clear-cut clinical scenarios, we retrospectively applied the selected cutoff values to the patients whose initial diagnosis in the ED was wrong (18 patients) or doubtful (14 patients). Four of these patients had non-cardiac dyspnoea and all showed NT-proBNP values <115 pmol/l (in two cases the NT-proBNP value was <30 pmol/l). Ventricular dysfunction was identified in 28 patients, of whom eight had decompensated heart failure and 20 masked heart failure. In this group, an NT-proBNP value >115 pmol/l correctly identified 87.5% of patients with decompensated heart failure and 85% with masked heart failure.

3.3. NT-proBNP levels at 24 h and 7 days
NT-proBNP levels were measured during hospitalization to monitor changes after onset of therapy. Table 2 shows NT-proBNP values obtained at 24 h and 7 days after admission to the ED. A significant and similar reduction in NT-proBNP levels was observed at day 7 in the two groups of patients with ventricular dysfunction (decompensated and masked heart failure) (P<0.001 and P<0.01 compared with admission values, respectively). Patients with non-cardiac dyspnoea showed no significant reduction in NT-proBNP concentrations during the first week of admission.

At day 7, after intensive medical therapy, we found complete resolution of the acute event in 30 patients with ventricular dysfunction (40%), stabilization of signs and symptoms to the chronic status in 31 patients (42%) and persistent decompensated heart failure in 13 patients (18%). Interestingly, complete clinical resolution occurred in 48% of patients with decompensated heart failure, but only in 18% of patients with masked heart failure (P<0.05). Fig. 3 shows the relative reduction in NT-proBNP values according to the clinical course during hospitalization. The greatest reduction in NT-proBNP concentrations of 56% was found in patients with complete resolution, a reduction of 37% was found in patients with clinical stabilization and a mean reduction of only 21% was found in patients with persistent decompensated heart failure. NT-proBNP relative reduction was significantly different between patients with complete resolution and those with persistent decompensated heart failure (P<0.05).


Figure 3
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  		Fig. 3 Percent reduction in NT-proBNP levels according to the clinical course during hospitalization. NT-proBNP levels were significantly lower in patients with complete resolution than in patients with insufficient response to therapy (P<0.05).

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study shows that NT-proBNP is a powerful predictor of ventricular dysfunction in patients attending the ED for acute dyspnoea. Measurement of NT-proBNP concentrations improves the ability of clinicians to differentiate patients with dyspnoea due to ventricular dysfunction from those with dyspnoea due to other causes in acute care settings. This is especially valuable among patients in whom the diagnosis of heart failure is not clinically straightforward. In our series, the ED physician erroneously diagnosed 18 patients and assigned to 14 patients a doubtful diagnosis. Of these, all the non-cardiac patients had an NT-proBNP value <115 pmol/l (in 2 NT-proBNP was <30 pmol/l), and in 87.5% and 85% of patients with decompensated or masked heart failure, respectively, the NT-proBNP concentration was >115 pmol/l. Thus, in our group of patients NT-proBNP could have contributed to a rapid and accurate diagnosis, which is mandatory in the ED to initiate the most appropriate treatment to alleviate symptoms and prolong survival. In this regard, Wuerz and Meador found that patients attending the ED with dyspnoea of respiratory origin had higher-than-expected mortality if initially misdiagnosed and erroneously treated for heart failure [15].

The NT-proBNP concentrations found in non-cardiac patients with dyspnoea were significantly higher than those of our control cohort. Two explanations are proposed. First, the clinical scenario of patients with acute and severe dyspnoea is driven by hypoxia and sympathetic overdrive. These phenomena may interact with cardiac function despite there being a structurally normal heart assessed by a non-invasive imaging technique. Furthermore, this is supported by the non-significant but persisting NT-proBNP decrease from 50 pmol/l on admission to 29 pmol/l at day 7 as the patient became clinically more stable. Second, 73% of patients with non-cardiac dyspnoea had a history of COPD, a known cause of low-level increase in natriuretic peptides [16].

In a population similar to ours but including patients with NYHA I–IV, similar results have been reported with BNP [13,17]. The authors concluded that rapid measurement of BNP used in conjunction with clinical information is useful in establishing or excluding the diagnosis of heart failure in patients with acute dyspnoea. There is no clear superiority of BNP over NT-proBNP for the diagnosis of LV dysfunction [11], as prognostic markers after myocardial infarction [18] or advanced LV dysfunction during pharmacological therapy [19]. Indeed, there is a good analytical agreement between BNP and NT-proBNP, but NT-proBNP circulates at higher concentrations than BNP [12], shows less intra-individual variability and may also be useful for monitoring of ventricular function in patients treated with BNP analogues (e.g. Nesiritide). Perhaps the reason NT-proBNP has not been used more often is that, until recently, the assay for NT-proBNP was not feasibile for most clinical laboratories. The assay we used in this study permits a rapid determination of NT-proBNP in less than 20 min, a convenient turn-around time for rapid management of patients presenting with dyspnoea to the ED. A recent study by Lainchbury et al. confirmed that measurement of BNP and N-BNP are useful in the diagnosis of heart failure in patients presenting to the emergency department with shortness of breath [20].

Analysis of the area under the ROC curve of the current data suggests that a NT-proBNP cutoff value of 115 pmol/l provides an excellent ability to discriminate ventricular dysfunction from subjects with normal hearts. This diagnostic threshold gives a sensitivity of 90%, specificity of 93% and diagnostic accuracy of 91.8%, with an area under the ROC curve of 0.957. The usefulness of NT-proBNP is stressed by the fact that in multivariate analysis NT-proBNP concentration was the variable with the highest odds ratio (45.4) to independently predict ventricular dysfunction. However, as with other biomarkers, relying on a single cutoff value may limit test utility. Using the cutoff of 115 pmol/l may have some limitations in an acute care setting, since it has a negative predictive value of only 70% to rule out patients with dyspnoea and normal heart function. Thus, it is possible that both a high and a low cutoff may be desired; a high one (115 pmol/l) for its specificity and positive predictive value, and a low value (30 pmol/l) for its high sensitivity and negative predictive value. A lower cutoff may be especially valuable in its negative predictive value for screening normal hearts in breathless patients. The level of 30 pmol/l as a rule-out cutoff value for dyspnoea of cardiac origin is strengthened by the fact that it coincides with the 95th percentile of our control cohort (31 pmol/l). Recently, James et al. reported in a reference population of the FRISC-II study a 97.5th percentile of 34 pmol/l [21].

Mean NT-proBNP concentrations increase with the severity of ventricular dysfunction [22–24] and heart failure [25,26]. As a continuation of these findings, this study provides direct evidence for a relationship between NT-proBNP concentrations measured at day 7 and subsequent improvement in the symptoms that motivated admission. NT-proBNP values remained higher and decreased less (mean reduction 21%) in patients with an unfavorable course than in patients with complete resolution of symptoms, in whom a 56% reduction in NT-proBNP was observed. In other words, in conjunction with the clinical signs and symptoms, NT-proBNP emerges as a valuable marker to monitor the response to therapy during hospitalization. Troughton et al. [27,28] demonstrated that drug treatment guided by plasma NT-proBNP concentrations reduced the total number of cardiovascular events compared with clinically-guided treatment by the same range of therapies. Their results indicate that treatment to lower NT-proBNP was beneficial in a group of patients with ejection fraction <40% and established symptomatic heart failure. Perhaps patients attending the ED with acute dyspnoea and high NT-proBNP levels should be treated intensively with vasodilators and diuretics, irrespective of the magnitude of clinical signs and symptoms of heart failure.

The increased mechanical stress manifested by augmented myocardial stretch from volume or pressure overload both play a role in the release kinetics of BNP and NT-proBNP [29]. This pathophysiology may also explain the positive association between NT-proBNP and troponin T found in this study. NT-proBNP concentration was higher in patients with ventricular dysfunction and positive cTnT (≥0.04 µg/l) than in those with ventricular dysfunction but negative cTnT (<0.04 µg/l). The role of both BNP [30] and NT-proBNP [31] as myocardial damage markers during acute coronary syndromes has been demonstrated.

In summary, NT-proBNP is a new candidate marker for the exclusion and detection of ventricular dysfunction, clinically evident or masked, in patients attending the ED for dyspnoea. In addition, our data indicate that NT-proBNP concentrations remain higher in those patients with a worse outcome during the first week of hospitalization. Accordingly, therapy might be guided by NT-proBNP concentrations during admission. Although the current predictive values support NT-proBNP as one of the best available biochemical markers of ventricular dysfunction, a possible strategy toward further improvement might be the combined assessment of several neurohormones and should be explored in additional studies.


   Acknowledgements
 
We thank J. Cinca and F. González-Sastre for critical review of the manuscript, and I. Gich for statistical assistance.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} Drs Bayés-Genis, Santaló-Bel, Zapico-Muñiz and Ordóñez-Llanos received honoraria from Roche Diagnostics for conferences. Roche Diagnstics kindly provided the reagents for this study. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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