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Articles |
1
Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132.
2
ARUP Institute for Experimental and Clinical Pathology,
Salt Lake City, UT 84108.
3
Departments of Laboratory Medicine and Pathology,
Children’s Hospital and Harvard Medical School, Boston, MA 02115.
4
Departments of Pathology and
5
Biochemistry
and Molecular Genetics, University of Virginia Health Science Center,
Charlottesville, VA 22908.
a Address correspondence to this author at: c/o ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108. Fax 801-584-5207; e-mail
william.roberts{at}arup-lab.com.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: Nine high-sensitivity CRP (hs-CRP) methods from Dade Behring, Daiichi, Denka Seiken, Diagnostic Products Corporation, Iatron, Kamiya, Olympus, Roche, and Wako were evaluated for limit of detection, linearity, precision, prozone effect, and comparability with samples from 388 apparently healthy individuals.
Results: All methods had limits of detection that were lower than the manufacturers’ claimed limit of quantification except for the Kamiya, Roche, and Wako methods. All methods were linear at 0.3–10 mg/L. The Diagnostic Products Corporation, Kamiya, Olympus, and Wako methods had imprecision (CVs) >10% at 0.15 mg/L. The Iatron, Olympus, and Wako methods demonstrated prozone effects at hs-CRP concentrations of 12, 206, and 117 mg/L, respectively. hs-CRP concentrations demarcating each quartile in a healthy population were method-dependent. Ninety-two to 95% of subjects were classified into the same quartile of hs-CRP established by the Dade Behring method by the Denka Seiken, Diagnostic Products Corporation, Iatron, and Wako methods. In contrast, 68–77% of subjects were classified into the same quartile by the Daiichi, Kamiya, Olympus, and Roche methods. No subject varied by more than one quartile by any method.
Conclusions: Four of the nine examined hs-CRP methods classified apparently healthy subjects into quartiles of hs-CRP similar to the classifications assigned by the comparison method. Additional standardization efforts are required because an individual patient’s results will be interpreted using population-based cutpoints.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chronic inflammation is an important component in the development and progression of atherosclerosis [for recent reviews, see Refs. (1)(2)]. Numerous epidemiologic studies have demonstrated that increased serum CRP concentrations are positively associated with risk of future coronary events. Included in this list are several studies conducted in large populations of apparently healthy men and women who subsequently developed coronary artery disease, cerebrovascular disease, or peripheral arterial disease (3)(4)(5)(6)(7)(8)(9). CRP has also been shown to be predictive of future events in patients with acute coronary syndromes and in patients with stable angina and coronary artery stents (10)(11)(12)(13)(14)(15).
Different methods for quantifying CRP in serum have been used. Studies conducted with apparently healthy individuals require high-sensitivity CRP (hs-CRP) methods. Relative risk of future coronary events can then be determined using hs-CRP cutpoints established in prospective epidemiologic studies. These high-sensitivity methods initially used ELISA methodology, and a single in-house ELISA assay was used for several population studies (3)(4)(16). This methodology is primarily for research and is not ideal for routine use in highly automated clinical laboratories. Traditional CRP methods in the clinical laboratory lack the desired sensitivity and, therefore, are unsuitable for the purpose of predicting future risk of coronary events in apparently healthy individuals. A latex-enhanced immunonephelometric hs-CRP method has recently been evaluated and validated clinically (17)(18). More recently, several automated immunoturbidimetric and immunoluminometric hs-CRP assays have been developed and are commercially available. These assays possess improved sensitivity and precision at low concentrations of CRP. In this study, we build on an earlier report (19) and describe the performance characteristics of nine hs-CRP methods, including method comparability, using samples from 388 adult blood donors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50 mg/L were used to investigate the prozone and
high-dose hook effects. Serum was separated from the red cells and
stored at -70 °C until analysis. All studies with samples from
human subjects were approved by the Institutional Review Board of the
University of Utah Health Sciences Center.
apparatus
The BN II nephelometer was from Dade Behring, the IMMULITE 2000
analyzer was from Diagnostics Products Corporation (DPC), the Hitachi
911 and 917 analyzers were from Roche Diagnostics, and the Olympus AU
640 analyzer was from Olympus USA.
assay procedures
Information for each of the nine methods is summarized in Table 1
. In all cases the manufacturers’ reagents were used as
directed. Analyses by the DPC method were performed using manual sample
dilution because of the limited sample volumes that were available for
this study. The Dade Behring BN II N High Sensitivity CRP assay was
used as the comparison method based on previous analytical and clinical
validations (17)(18)(19). At the time of manuscript submission,
only the Dade Behring and Kamiya methods had been approved by the Food
and Drug Administration (FDA) for clinical use in the United States,
and only the Dade Behring assay had been approved by the FDA for use in
assessing the risk of cardiovascular and peripheral vascular disease
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The limit of detection of each method was assessed by analyzing a zero
calibrator 20 times and calculating a 2 SD limit. Samples for linearity
and lower limits of quantification were prepared from two serum pools.
The low pool was prepared by combining samples from blood donors with
hs-CRP concentrations in the lowest quartile. The high pool was
prepared by combining patient samples with hs-CRP concentrations of
10 mg/L. The high pool was diluted with the low pool to the
following final percentages of the high pool: 100%, 75%, 50%, 30%,
20%, 10%, 5%, 2.5%, and 0%. Samples were assayed in duplicate in
one analytical run. Five samples were used for imprecision studies.
Level 1 and level 5 were prepared using a solution containing 60
g/L bovine serum albumin and adding purified CRP (Sigma).
Levels 2 and 4 were Kamiya calibrators with assigned values of 0.5 and
1.5 mg/L, respectively. Level 3 was serum obtained from a single
subject. Each sample was run in duplicate on 5 different days, and the
total imprecision was calculated.
data analysis
EP Evaluator-CLIA software (David G. Rhoads Associates, Kennett
Square, PA) was used for Deming regression analysis, calculation of
r and Sy|x, and linearity assessment.
Identical representative standard deviations were used for the
x and y methods. An allowable systematic error
limit of 10% was chosen for the linearity assessment, and the limit of
quantification was the lowest measured concentration that fulfilled
this criterion. hs-CRP concentrations were skewed rightward in samples
from blood donors; therefore, percentile values were estimated and
hs-CRP concentrations were log-transformed for method comparison plots.
Probabilities for the t-test were calculated using Primer of
Bio-statistics: The Program, Ver. 4.02 (Stanton A. Glantz, author,
McGraw-Hill Companies).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The limits of detection of the Kamiya (0.32
mg/L), Roche (0.21 mg/L), and Wako (0.06 mg/L) assays did not achieve
the manufacturers’ claimed limit of detection, although the Wako
method was very close to that claimed. These minor discrepancies could
be related to how the limit of detection was defined by the
manufacturer or to the particular analyzer used in this study.
To examine the linearity of each method, samples were prepared from two
serum pools as described in Materials and Methods. All
assays were linear to the lowest concentration tested, which was a pool
of the samples from the lowest quartile of hs-CRP concentrations from
blood donors, except for the Denka method, which was linear down to
0.23 mg/L, using a 10% systematic error limit (Table 1
). The range of
values observed for the low pool was 0.07–0.30 mg/L, and the range of
values observed for the high pool was 8.01–12.1 mg/L. Regression
analysis of the data yielded intercepts of 0.00–0.30 mg/L, which were
comparable to the measured values for the low pool (data not shown).
To quantify the imprecision of the nine methods in the hs-CRP
concentration range of the reference interval, samples containing five
concentrations of hs-CRP were assayed in duplicate on 5 different days
(Table 2
). The DPC, Kamiya, Olympus, and Wako methods all had CVs >10%
at a CRP concentration of 0.15 mg/L. The imprecision of each method
improved at a CRP concentration of 0.5 mg/L, and all assays had CVs
<10% at this concentration except for the Olympus method. This method
achieved a CV <10% at a CRP concentration of 0.6 mg/L.
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Samples with very high CRP concentrations were analyzed to test each method for susceptibility to falsely low results with very high CRP concentrations caused by either a prozone effect for the single antibody nephelometric and turbidimetric methods or a high-dose hook effect for the double antibody luminometric method. The DPC method showed no evidence of a hook effect at the highest CRP concentration tested, which was 480 mg/L. The Dade Behring, Daiichi, Denka Seiken, Kamiya, and Roche methods showed no evidence of a prozone effect at CRP concentrations up to 480 mg/L. The Iatron, Olympus, and Wako methods showed evidence of prozone effects at CRP concentrations of <50, 206, and 117 mg/L, respectively. Additional samples were analyzed, and the Iatron method demonstrated a prozone effect at CRP concentrations as low as 12 mg/L.
The hs-CRP concentrations of 388 serum samples collected from
apparently healthy adult blood donors were measured by all nine methods
simultaneously. Inspection of the data revealed a highly skewed
population. Therefore, values for the 25th, 50th, 75th, 80th,
90th, 95th, and 97.5th percentile were determined for each method
(Table 3
).
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The agreement of the nine methods with samples from apparently healthy
individuals donors was assessed graphically (Fig. 1
). The Dade Behring method had previously been compared with an
in-house ELISA method that was used in several hs-CRP epidemiologic
studies and has been validated clinically
(6)(17)(18); it currently is being
used in several prospective epidemiological studies and clinical
trials, including the Nurses’ Health Study, Women’s Health
Study, Health Professionals’ Study, Women’s Health Initiative, Air
Force/Texas Coronary Atherosclerosis Prevention Study, and Cholesterol
and Recurrent Events. Furthermore, at the time this study was
initiated, it was the only method approved by the FDA for
cardiovascular and peripheral vascular risk assessment. Therefore, it
was chosen as the comparison method for evaluating the other eight
methods. Visual inspection of the log-log plots indicated good
concordance between the Denka Seiken, DPC, Iatron, Kamiya, Roche, and
Wako methods and the comparison method (Fig. 1
). The Daiichi and
Olympus methods showed more scatter for results that were less than the
median value. Deming regression analysis was performed on all data
before log transformation (Table 4
).
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To better compare concordance among methods, the distribution of hs-CRP
results from the studied population measured by each of the eight new
methods was examined within the quartile cutpoints established by the
Dade Behring assay. The results of this analysis (Fig. 2
) indicate there are two groups of methods. The first group,
which agrees the best with the Dade Behring method, included the Denka
Seiken, DPC, Iatron, and Wako methods. The agreement between these
methods and the comparison method in quartile assignments was 92–95%.
The second group, which gave slightly higher hs-CRP results, consisted
of the Daiichi, Olympus, Kamiya, and Roche methods. The agreement
between these methods and the comparison method in quartile assignments
was 68–77%. However, in no case did any result disagree with the
quartile assignment of the Dade Behring method by more than one
quartile. Statistical analysis of the agreement between the Dade
Behring method and the other eight methods for each quartile was
performed (20). The results (Table 5
) indicate that the mean differences for the lowest three
quartile were <0.1 mg/L for the Denka Seiken, DPC, Iatron, and Wako
methods and >0.1 mg/L for the Daiichi, Kamiya, Olympus, and Roche
methods. The Daiichi, Kamiya, Olympus, and Roche methods showed
statistically significant differences from the comparative method
(P <0.001) for the three lowest quartiles. The Denka Seiken
method showed a statistically significant difference from the
comparative method for the second quartile (P = 0.022).
The Iatron method showed a statistically significant difference from
the comparative method for the first quartile (P =
0.048).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and both
assays had CVs 
15% at these CRP concentrations (Table 2
).
Criteria for both accuracy and precision need to be clearly defined.
hs-CRP results will be interpreted in quartiles or quintiles for risk
assessment (21). Therefore, hs-CRP assays will need to be
standardized for concentrations of 0.2–10 mg/L so that results
obtained in large population studies can be applied to individual
patients. All nine methods we evaluated were linear over this
concentration range.
A definition of functional assay sensitivity similar to that used for
measurement of thyroid-stimulating hormone is required to
ensure that assays have the requisite precision at low CRP
concentrations. We previously proposed that for risk stratification for
cardiovascular, cerebrovascular, and peripheral vascular disease, the
hs-CRP assay imprecision should be <10% at a concentration of 0.2
mg/L (19). The methods we evaluated all had CVs <10% at an
hs-CRP concentration of 0.15 mg/L except for the DPC, Kamiya, Olympus,
and Wako methods. This lack of precision at low CRP concentrations was
most noticeable for the Olympus method when results from blood donors
were compared (Fig. 2F
). When reviewing the precision data in Table 2
,
it is noteworthy that different protein-based matrices yielded
different relative recoveries. Levels 2 and 4 were calibrators from the
Kamiya method with assigned values of 0.5 and 1.5 mg/L, respectively.
Mean values determined by each of the nine methods were within -18%
and 14% of the mean of all methods. For level 3, which was serum from
a single subject, mean values for each method ranged from -31% to
28% of the mean calculated for all methods. These results suggest that
even liquid-stabilized protein-based calibrators do not simulate the
matrix of human serum samples. These matrix effects may contribute to
the lack of standardization between methods.
Several previous studies that examined serum hs-CRP concentrations in apparently healthy populations using highly sensitive ELISA, nephelometric, and turbidimetric methods found median values ranging from 0.58 to 1.13 mg/L (3)(5)(17)(22)(23)(24)(25). Median values determined by the nine methods examined here were 0.78–1.14 mg/L, consistent with these earlier studies. Four of these studies found 75th percentile values of 1.44–2.10 mg/L, whereas we found values of 1.89–2.49 mg/L, consistent with the earlier studies (3)(23)(25). Two previous studies found the 90th percentile hs-CRP concentration to be 3 mg/L, and a third found a range for four methods of 4.1–5.3 mg/L, whereas we found values of 4.41–5.43 mg/L for the nine methods we investigated, consistent with earlier studies (19)(22)(23). Differences between the Dade Behring comparison method and results from the other eight methods for the 25th percentile ranged from -20% to 38% of the comparison method, results for the 50th percentile ranged from -13% to 27% of the comparison method, and results for the 75th percentile ranged from -6% to 25% of the comparison method. These results indicate that further standardization efforts are required if hs-CRP results from different methods are to be used interchangeably. These standardization activities will be similar to those conducted for cholesterol, whose concentration is also interpreted for the individual patient based on population-based cutpoints.
According to information provided by each of the assay manufacturers, all of the methods we investigated were standardized against the IFCC Certified Reference Material (CRM) 470 standard rather than against the older WHO International Reference Standard for CRP Immunoassay 85/506. The methods evaluated in this study could be divided into two groups based on their ability to classify subjects into quartiles of hs-CRP. For one group of methods, which included the Denka Seiken, DPC, Iatron, and Wako assays, 92–95% of subjects were classified into the same quartile of hs-CRP concentrations. Furthermore, these assays showed minimal or negative bias relative to the comparison method. In the other group, which included the Daiichi, Kamiya, Olympus, and Roche assays, 68–77% of subjects were classified into the same quartile of hs-CRP. In addition, substantial positive bias relative to the comparison method was noted. hs-CRP concentrations that correspond to the 75th percentile for this latter group are comparable to 80th percentile concentrations for the former group. It is important to indicate, however, that none of the examined subjects was misclassified by more than one quartile. Therefore, although more standardization is needed to harmonize the results from the various methods, the performance of the examined assays in this report is promising.
A previous comparison between the BN II and Hemagen ELISA methods showed a slope of 0.75 and an intercept of -0.25 mg/L (17). The BN II assay was standardized against CRM 470, whereas the Hemagen ELISA was standardized the WHO CRP reference material (24). Differences in standardization materials or the use of suboptimal value transfer protocols likely explain the difference between these two methods. We have made a similar observation with a different group of hs-CRP assays, all which claim to be standardized against the same CRM 470 material. These findings further support the earlier notion of standardizing hs-CRP assays at concentrations comparable to those seen in healthy subjects.
Another issue that merits discussion is the possibility of underestimating the true CRP concentration because of a prozone effect. The Iatron, Olympus, and Wako methods are particularly susceptible to this problem. A review of 2222 results for hs-CRP performed in a reference laboratory revealed that 55 (2.5%) had values >50 mg/L and 21 (0.9%) had values >100 mg/L. Ideally, one might have one CRP method that could routinely provide both high sensitivity and traditional measurements. This option might minimize confusion in ordering. Physicians could order a single test and obtain either an hs-CRP result for atherosclerotic risk prediction or a higher CRP result as an indicator of more severe inflammation. Of the methods examined in this report, the Dade Behring, Daiichi, and DPC assays currently best fulfill this criterion.
In conclusion, the nine examined methods exhibited some differences in their ability to classify apparently healthy subjects into quartiles of hs-CRP concentrations. Additional standardization efforts are required to further ensure that results obtained by automated hs-CRP methods on an individual patient can be interpreted using cutpoints established by prospective epidemiologic studies. Once standardization has been achieved, hs-CRP assays can provide useful data for coronary risk stratification in apparently healthy individuals.
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Acknowledgments |
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Footnotes |
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References |
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J. V. Callaghan and S. I. Gutman Counterpoint: food and drug administration guidance for C-reactive protein assays: matching claims with performance data. Clin. Chem., July 1, 2006; 52(7): 1256 - 1257. [Full Text] [PDF]
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 M. Takemura, H. Matsumoto, A. Niimi, T. Ueda, H. Matsuoka, M. Yamaguchi, M. Jinnai, S. Muro, T. Hirai, Y. Ito, et al. High sensitivity C-reactive protein in asthma. Eur. Respir. J., May 1, 2006; 27(5): 908 - 912. [Abstract] [Full Text] [PDF]
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A. Khera, J. A. de Lemos, R. M. Peshock, H. S. Lo, H. G. Stanek, S. A. Murphy, F. H. Wians Jr, S. M. Grundy, and D. K. McGuire Relationship Between C-Reactive Protein and Subclinical Atherosclerosis: The Dallas Heart Study Circulation, January 3, 2006; 113(1): 38 - 43. [Abstract] [Full Text] [PDF]
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W. Pitiphat, M. W. Gillman, K. J. Joshipura, P. L. Williams, C. W. Douglass, and J. W. Rich-Edwards Plasma C-Reactive Protein in Early Pregnancy and Preterm Delivery Am. J. Epidemiol., December 1, 2005; 162(11): 1108 - 1113. [Abstract] [Full Text] [PDF]
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C. M. Ballantyne, R. C. Hoogeveen, H. Bang, J. Coresh, A. R. Folsom, L. E. Chambless, M. Myerson, K. K. Wu, A. R. Sharrett, and E. Boerwinkle Lipoprotein-Associated Phospholipase A2, High-Sensitivity C-Reactive Protein, and Risk for Incident Ischemic Stroke in Middle-aged Men and Women in the Atherosclerosis Risk in Communities (ARIC) Study Arch Intern Med, November 28, 2005; 165(21): 2479 - 2484. [Abstract] [Full Text] [PDF]
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N. Lamblin, F. Mouquet, B. Hennache, J. Dagorn, S. Susen, C. Bauters, and P. de Groote High-sensitivity C-reactive protein: potential adjunct for risk stratification in patients with stable congestive heart failure Eur. Heart J., November 1, 2005; 26(21): 2245 - 2250. [Abstract] [Full Text] [PDF]
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 F. Mittermayer, J. Pleiner, G. Schaller, S. Zorn, K. Namiranian, S. Kapiotis, G. Bartel, M. Wolfrum, M. Brugel, J. Thiery, et al. Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1752 - H1757. [Abstract] [Full Text] [PDF]
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A. Khera, D. K. McGuire, S. A. Murphy, H. G. Stanek, S. R. Das, W. Vongpatanasin, F. H. Wians Jr, S. M. Grundy, and J. A. de Lemos Race and Gender Differences in C-Reactive Protein Levels J. Am. Coll. Cardiol., August 2, 2005; 46(3): 464 - 469. [Abstract] [Full Text] [PDF]
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 C. Liu, S. Wang, A. Deb, K. A. Nath, Z. S. Katusic, J. P. McConnell, and N. M. Caplice Proapoptotic, Antimigratory, Antiproliferative, and Antiangiogenic Effects of Commercial C-Reactive Protein on Various Human Endothelial Cell Types In Vitro: Implications of Contaminating Presence of Sodium Azide in Commercial Preparation Circ. Res., July 22, 2005; 97(2): 135 - 143. [Abstract] [Full Text] [PDF]
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P. M Ridker, N. Rifai, N. R. Cook, G. Bradwin, and J. E. Buring Non-HDL Cholesterol, Apolipoproteins A-I and B100, Standard Lipid Measures, Lipid Ratios, and CRP as Risk Factors for Cardiovascular Disease in Women JAMA, July 20, 2005; 294(3): 326 - 333. [Abstract] [Full Text] [PDF]
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M. Di Napoli, M. Schwaninger, R. Cappelli, E. Ceccarelli, G. Di Gianfilippo, C. Donati, H. C.A. Emsley, S. Forconi, S. J. Hopkins, L. Masotti, et al. Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke: A Statement for Health Care Professionals From the CRP Pooling Project Members Stroke, June 1, 2005; 36(6): 1316 - 1329. [Abstract] [Full Text] [PDF]
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H. Hakonarson, S. Thorvaldsson, A. Helgadottir, D. Gudbjartsson, F. Zink, M. Andresdottir, A. Manolescu, D. O. Arnar, K. Andersen, A. Sigurdsson, et al. Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial JAMA, May 11, 2005; 293(18): 2245 - 2256. [Abstract] [Full Text] [PDF]
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G. L. Myers, N. Rifai, R. P. Tracy, W. L. Roberts, R. W. Alexander, L. M. Biasucci, J. D. Catravas, T. G. Cole, G. R. Cooper, B. V. Khan, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Laboratory Science Discussion Group Circulation, December 21, 2004; 110(25): e545 - e549. [Full Text] [PDF]
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W. L. Roberts CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Laboratory Tests Available to Assess Inflammation--Performance and Standardization: A Background Paper Circulation, December 21, 2004; 110(25): e572 - e576. [Abstract] [Full Text] [PDF]
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R. Rej Clinical Chemistry through Clinical Chemistry: A Journal Timeline Clin. Chem., December 1, 2004; 50(12): 2415 - 2458. [Abstract] [Full Text] [PDF]
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 K. D. Monahan, T. E. Wilson, and C. A. Ray Omega-3 Fatty Acid Supplementation Augments Sympathetic Nerve Activity Responses to Physiological Stressors in Humans Hypertension, November 1, 2004; 44(5): 732 - 738. [Abstract] [Full Text] [PDF]
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D. Fliser, K. Buchholz, H. Haller, and for the EUropean Trial on Olmesartan and Pravastat Antiinflammatory Effects of Angiotensin II Subtype 1 Receptor Blockade in Hypertensive Patients With Microinflammation Circulation, August 31, 2004; 110(9): 1103 - 1107. [Abstract] [Full Text] [PDF]
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B. Schieffer, C. Bunte, J. Witte, K. Hoeper, R. H. Boger, E. Schwedhelm, and H. Drexler Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease J. Am. Coll. Cardiol., July 21, 2004; 44(2): 362 - 368. [Abstract] [Full Text] [PDF]
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 J. Danesh, J. G. Wheeler, G. M. Hirschfield, S. Eda, G. Eiriksdottir, A. Rumley, G. D.O. Lowe, M. B. Pepys, and V. Gudnason C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease N. Engl. J. Med., April 1, 2004; 350(14): 1387 - 1397. [Abstract] [Full Text] [PDF]
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C. M. Ballantyne, R. C. Hoogeveen, H. Bang, J. Coresh, A. R. Folsom, G. Heiss, and A. R. Sharrett Lipoprotein-Associated Phospholipase A2, High-Sensitivity C-Reactive Protein, and Risk for Incident Coronary Heart Disease in Middle-Aged Men and Women in the Atherosclerosis Risk in Communities (ARIC) Study Circulation, February 24, 2004; 109(7): 837 - 842. [Abstract] [Full Text] [PDF]
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C. Chiesa, A. Panero, J. F. Osborn, A. F. Simonetti, and L. Pacifico Diagnosis of Neonatal Sepsis: A Clinical and Laboratory Challenge Clin. Chem., February 1, 2004; 50(2): 279 - 287. [Full Text] [PDF]
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G. J. Blake, N. Rifai, J. E. Buring, and P. M Ridker Blood Pressure, C-Reactive Protein, and Risk of Future Cardiovascular Events Circulation, December 16, 2003; 108(24): 2993 - 2999. [Abstract] [Full Text] [PDF]
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N. Khuseyinova, A. Imhof, G. Trischler, D. Rothenbacher, W. L. Hutchinson, M. B. Pepys, and W. Koenig Determination of C-Reactive Protein: Comparison of Three High-Sensitivity Immunoassays Clin. Chem., October 1, 2003; 49(10): 1691 - 1695. [Full Text] [PDF]
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T. B. Ledue and N. Rifai Preanalytic and Analytic Sources of Variations in C-reactive Protein Measurement: Implications for Cardiovascular Disease Risk Assessment Clin. Chem., August 1, 2003; 49(8): 1258 - 1271. [Abstract] [Full Text] [PDF]
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E. S. Ford, W. H. Giles, G. L. Myers, N. Rifai, P. M. Ridker, and D. M. Mannino C-reactive Protein Concentration Distribution among US Children and Young Adults: Findings from the National Health and Nutrition Examination Survey, 1999-2000 Clin. Chem., August 1, 2003; 49(8): 1353 - 1357. [Abstract] [Full Text] [PDF]
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M. A. Albert, R. J. Glynn, and P. M Ridker Plasma Concentration of C-Reactive Protein and the Calculated Framingham Coronary Heart Disease Risk Score Circulation, July 15, 2003; 108(2): 161 - 165. [Abstract] [Full Text] [PDF]
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Y.-C. Tsen, G.-Y. Kao, C.-L. Chang, F.-Y. Lai, C.-H. Huang, S. Ouyang, M.-H. Yu, C.-P. Wang, and Y-N. Chiou Evaluation and Validation of a Duck IgY Antibody-based Immunoassay for High-Sensitivity C-reactive Protein: Avian Antibody Application in Clinical Diagnostics Clin. Chem., May 1, 2003; 49(5): 810 - 813. [Full Text] [PDF]
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M. M. Kimberly, H. W. Vesper, S. P. Caudill, G. R. Cooper, N. Rifai, F. Dati, and G. L. Myers Standardization of Immunoassays for Measurement of High-Sensitivity C-reactive Protein. Phase I: Evaluation of Secondary Reference Materials Clin. Chem., April 1, 2003; 49(4): 611 - 616. [Abstract] [Full Text] [PDF]
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N. Rifai and P. M. Ridker Population Distributions of C-reactive Protein in Apparently Healthy Men and Women in the United States: Implication for Clinical Interpretation Clin. Chem., April 1, 2003; 49(4): 666 - 669. [Full Text] [PDF]
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P. M Ridker Clinical Application of C-Reactive Protein for Cardiovascular Disease Detection and Prevention Circulation, January 28, 2003; 107(3): 363 - 369. [Full Text] [PDF]
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T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. Criqui, Y. Y. Fadl, S. P. Fortmann, Y. Hong, G. L. Myers, et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association Circulation, January 28, 2003; 107(3): 499 - 511. [Full Text] [PDF]
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M. A. Albert, R. J. Glynn, and P. M Ridker Alcohol Consumption and Plasma Concentration of C-Reactive Protein Circulation, January 28, 2003; 107(3): 443 - 447. [Abstract] [Full Text] [PDF]
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P. M. Ridker, N. Rifai, L. Rose, J. E. Buring, and N. R. Cook Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular Events N. Engl. J. Med., November 14, 2002; 347(20): 1557 - 1565. [Abstract] [Full Text] [PDF]
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J. Middleton Effect of Analytical Error on the Assessment of Cardiac Risk by the High-Sensitivity C-Reactive Protein and Lipid Screening Model Clin. Chem., November 1, 2002; 48(11): 1955 - 1962. [Abstract] [Full Text] [PDF]
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 P. Garnero, C. Jamin, C.-L. Benhamou, C. Pelissier, and C. Roux Effects of tibolone and combined 17{beta}-estradiol and norethisterone acetate on serum C-reactive protein in healthy post-menopausal women: a randomized trial Hum. Reprod., October 1, 2002; 17(10): 2748 - 2753. [Abstract] [Full Text] [PDF]
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A. D. Blann, P. M. Ridker, and G. Y.H. Lip Inflammation, Cell Adhesion Molecules, and Stroke: Tools in Pathophysiology and Epidemiology? Stroke, September 1, 2002; 33(9): 2141 - 2143. [Full Text] [PDF]
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M. Ishibashi, Y. Takemura, H. Ishida, K. Watanabe, and T. Kawai C-Reactive Protein Kinetics in Newborns: Application of a High-Sensitivity Analytic Method in Its Determination Clin. Chem., July 1, 2002; 48(7): 1103 - 1106. [Full Text] [PDF]
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S. Rothkrantz-Kos, M. P.J. Schmitz, O. Bekers, P. P.C.A. Menheere, and M. P. van Dieijen-Visser High-Sensitivity C-Reactive Protein Methods Examined Clin. Chem., February 1, 2002; 48(2): 359 - 362. [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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R. S. Ayash Re: Europium nanoparticles and time-resolved fluorescence for ultrasensitive detection of prostate-specific antigen. Clin. Chem., September 1, 2001; 47(9): 1743 - 1744. [Full Text] [PDF]
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M. A. Albert, E. Danielson, N. Rifai, P. M Ridker, and for the PRINCE Investigators Effect of Statin Therapy on C-Reactive Protein Levels: The Pravastatin Inflammation/CRP Evaluation (PRINCE): A Randomized Trial and Cohort Study JAMA, July 4, 2001; 286(1): 64 - 70. [Abstract] [Full Text] [PDF]
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P. M. Ridker High-Sensitivity C-Reactive Protein : Potential Adjunct for Global Risk Assessment in the Primary Prevention of Cardiovascular Disease Circulation, April 3, 2001; 103(13): 1813 - 1818. [Abstract] [Full Text] [PDF]
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