C a rd i a c Tro p o n i n s a n d H i g h s e n s i t i v i t y C a rd i a c Tro p o n i n Assays Michael J. Conrad,
ALM,
Petr Jarolim,
MD, PhD*
KEYWORDS Cardiac markers Cardiac troponin High-sensitivity assay Biomarker Acute myocardial infarction Adverse event Risk prediction KEY POINTS This article discusses: The classification of cardiac troponin I and T assays according to their sensitivity. The requirement of the universal definition of myocardial infarction to establish the increase and/or decrease in cardiac troponin concentrations in patients and the 99th percentile of cardiac troponin concentrations in healthy individuals. Applications of high-sensitivity cardiac troponin assays for short-term and long-term prediction of adverse cardiovascular events.
INTRODUCTION
The development and ongoing implementation of the high-sensitivity cardiac troponin assays has generated considerable interest. Increased sensitivity offers opportunities for greatly improved diagnostics, but some clinicians are concerned about the reduced specificity of these assays. This article discusses the impact of the gradual implementation of high-sensitivity cardiac troponin assays on the clinical diagnostics of acute coronary syndrome (ACS), as well as short-term and long-term prognosis of adverse cardiovascular events. The structure and function of cardiac troponins are also reviewed.
Disclosure Statement: P. Jarolim received consulting income from T2 Biosystems and Quanterix, and research support from Abbott, AstraZeneca, Daiichi Sankyo, Merck, Roche Diagnostics, and Waters Technologies; M.J. Conrad received consulting income from Quanterix. Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Harvard Medical School, Boston, MA 02115, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med 34 (2014) 59–73 http://dx.doi.org/10.1016/j.cll.2013.11.008 labmed.theclinics.com 0272-2712/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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STRUCTURE AND FUNCTION OF CARDIAC TROPONINS Components of the Cardiac Troponin Complex
Troponins are arranged in a heterotrimeric complex consisting of 3 troponin molecules, whose names are derived from their functions: calcium-binding troponin C (TnC; 18 kDa), inhibitory troponin I (TnI; 24 kDa), and tropomyosin-binding troponin T (TnT; 37 kDa). The complex attaches to the thin filaments of muscle and acts to regulate muscle contraction. The troponin isoforms expressed in muscle tissues differ based on the tissue’s role, with the cardiac myocyte uniquely expressing the cardiac TnI (cTnI) and cardiac troponin T (cTnT) isoforms. This tissue specificity has driven the use of cardiac troponins as biomarkers for cardiac injury. Although there is a so-called cardiac troponin C (cTnC), it is expressed in both cardiac and slow skeletal muscle.1 The troponin complex plays an essential role in regulating the excitation-contraction coupling in skeletal and cardiac muscle through calcium signaling. Without calcium bound by TnC, the TnI protein binds the heterotrimer closely to the thin filament. The binding of calcium by TnC causes a conformational change, exposing a hydrophobic section to which TnI preferentially binds. In doing so, the complex is able to swing away from the thin filament, allowing TnT to bind tropomyosin, and exposing actin binding sites that previously were covered by TnI. This process drives muscle contraction.1 Cardiac Troponin Genes
Three pairs of troponin genes are located adjacent to each other on chromosomes 1, 11, and 19. Cardiac troponins do not form a pair on the same chromosome. Instead, the cTnI gene, TNNI3, is located on chromosome 19, whereas the cTnT gene, TNNT2, is located on chromosome 1.1,2 Isoforms can be encoded by separate genes or created through alterative splicing.2,3 The troponins are generally well-conserved genes, and mutations in cTnI and cTnT have been implicated in the pathogenesis of several conditions, including hypertrophic cardiomyopathy.1,4 Cardiac Troponin Gene Expression
The expression of troponin differs significantly between the embryonic and adult hearts. Although cTnC is expressed consistently throughout life, slow skeletal TnI is expressed in the hearts of embryos along with some cTnI, transitioning after birth to cTnI alone by 9 months after birth.5,6 The process for cTnT is more complex, because a mix of TnT1 and TnT3 predominate in the embryo, shifting to TnT3 and TnT4 after birth.1 There is evidence of a tendency toward reverting to fetal expression patterns in the ailing heart, and there are some rare cases of cardiac troponin expression outside the heart, which complicates the overall picture.1,7 Translation and Posttranslational Modifications
Turnover of the three troponin proteins was found in rats to occur at different rates, perhaps because of the localization of the genes across separate chromosomes and because their half-lives range from 3 to 5 days.8,9 Replacement of the troponins seems to occur randomly along the thin filaments in differentiated adult rat cells, rather than in an ordered fashion, which implies that maintenance of these filaments is performed while maintaining functionality, allowing consistent cardiac activity.8 The action of cardiac troponins may be tuned through phosphorylation or cleavage, altering cardiac output potential.1,10 Troponin Release from Cardiac Myocytes
Most troponin is bound to thin filaments as part of the structural pool. A small portion is free in the cytoplasm as the cytoplasmic pool. The cytoplasmic pool is the likely
High-sensitivity Cardiac Troponin Assays
source of the initial increase in serum troponin after myocardial injury, with subsequent troponin being released from the degraded structural pool. The estimates for the size of the cytoplasmic pool differ widely, ranging from 3% to 8% of the total cellular troponin.11–13 The major forms of troponin released into circulation are cTnT and the cTnI-TnC complex. Additional forms found circulating in plasma are the cTnT-cTnITnC ternary complex and free cTnI.11,14 The mechanism of troponin release from cardiac myocytes, in the absence of acute injury, is not completely understood. Although the so-called troponin leak is frequently mentioned, there are no data explaining this term, and it is unlikely that the sizable troponin molecules are released into circulation from viable cardiac myocytes. Perhaps the only mechanism that would allow limited release of troponin and leave behind viable cardiac cells is the formation of exosomes containing small amounts of the free, cytoplasmic troponin. Formation of blebs in cardiac myocytes exposed to ischemia has been reported.15,16 In our opinion, the most likely mechanism leading to the presence of cardiac troponin in circulation is myocyte death occurring physiologically as part of the continuous renewal of cardiomyocytes. The process of cardiomyocyte renewal is generally accepted, although there are major discrepancies in the estimates of its rate. According to some investigators, the heart is replaced on average 11 to 15 times during a person’s lifetime,17 but according to other investigators, only 40% of the heart is replaced.18 After release from the myocyte, troponin is degraded, fragmented, and cleared. These processes are not fully understood, creating analytical challenges.16,19,20 CARDIAC TROPONIN ASSAYS History of Cardiac Troponin Immunoassays
The first cardiac-specific troponin I assay was described in 1987 by Cummins and colleagues,21 and the first commercial cTnI assay was brought to the market by Dade Behring for use on the Stratus I analyzer. Compared with this first investigational cTnI assay, current commercial troponin I assays are more than 1000 times more sensitive, with the sensitivity of the investigational assays an additional 10 to 100 times higher. The first cTnT assay was developed by Katus and colleagues22 in 1989. The initial limit of detection (LOD) was 500 ng/L. Again, sensitivity of the original assay is about 2 orders of magnitude lower than that of the current high-sensitivity TnT (hsTnT) assay, with a LOD of 3 ng/L. Standardization of Cardiac Troponin Immunoassays
Despite more than a decade of efforts to standardize cTnI assays from different manufacturers, only minor progress has been made. Fig. 1 shows the diverse combinations of capture and detecting antibodies for different cTnI assays, each with its own incubation conditions, heterophile blocking reagents, detection technologies, and standard materials, which illustrates why it is difficult to obtain identical numeric results for cTnI concentrations using immunoassays from different manufacturers. It is unlikely that standardization of cTnI assays will be accomplished soon.23 Standardization of the cTnT assay is not a major problem. Because of patent issues, the cTnT assay is only available from Roche Diagnostics, so the only inconvenience is the current coexistence of the less sensitive fourth-generation cTnT assay in the United States and the high-sensitivity hsTnT assay in most other countries. Nevertheless, although these two assays use the same monoclonal antibodies and should
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Fig. 1. The cTnI molecule (amino acids 1–210), stable central region,20 and antibody binding sites (capture in gray, detection in black) for selected assays from Table 1.
theoretically produce almost identical results, correlation at the low end is not linear, producing higher numerical results in the high-sensitivity assay compared with the fourth-generation cTnT.24 Another complication when interpreting results of certain studies using high-sensitivity assays is the recently reported miscalibration issue,25–28 which has led to underestimation of cTnT concentrations at the low end and potentially invalidated conclusions of certain studies. However, recalculation of results greater than LOD is possible and may be performed by Roche Diagnostics. Although cTnI and cTnT should be released from damaged cardiomyocytes in equimolar amounts, cTnI and cTnT correlate poorly, a situation that is worsened when accounting for multiple cTnI assays. This effect may be caused by several mechanisms: different stability of cTnI and cTnT in the circulation, different clearance rates in different patients, different ratio of free cTnI and cTnT pools in the cytoplasm of the damaged myocytes, and so forth. What Defines a High-sensitivity Cardiac Troponin Assay?
The large increase in sensitivity of cTn assays is shown in Fig. 2, which plots the limits of detection and 99th percentiles for 5 categories of cTn assays. We call the oldest, category, which is no longer used, low-sensitivity assays. These assays only detected the largest increases of cTn, without detecting other pathologic, albeit less dramatic, increases. We prefer to call the assays currently available in the United States medium sensitivity assays, although they have been referred to as contemporary assays.29 These assays reliably detect cTn increases to more than the 99th percentile, but are able to quantitate cTn in only a fraction of healthy individuals. Conventional troponin assays have had a clear performance goal of measuring troponin with a 10% coefficient of variation (CV) at the 99th percentile of their reference population. As manufacturers have worked to increase the sensitivity of their assays, the definition of high-sensitivity in cTn assays has changed. The International Federation of Clinical Chemistry (IFCC) task force suggested in 2012 that in order to label a cardiac troponin assay as highly sensitive, cTn should be measurable in more than 50% of healthy subjects, and preferably in more than 95%.30 We suggest that an ideal high-sensitivity assay should quantitate troponin in 100% of a healthy reference population and would have a 10% CV at the 10th percentile for the same population. This level of performance would make it possible to consider personal reference ranges or small delta values over short time frames for use in emergency
High-sensitivity Cardiac Troponin Assays
Fig. 2. Sensitivity of cardiac troponin assays. The effect of increasing cTnI assay sensitivity relative to a healthy population and the measured 99th percentile for each assay along with 10% and 20% coefficient of variation (CV) limits.
care. More importantly, it is not clear that performance in excess of this standard would be valuable in the clinical setting. The performance of current troponin assays is summarized in Table 1. We reserve the term ultrasensitive for assays capable of quantitating cTn at levels less than the lowest cTn concentrations seen in healthy individuals. Additional sensitivity may be beneficial for novel applications of the cTn assays, such as measuring cTn levels during diagnostic procedures31 or using them for early detection of druginduced cardiac toxicity in experimental animal models. Assays with improved sensitivity, such as the Abbott hsTnI and Roche hsTnT assays, have generally been developed using a variety of standard steps taken to improve immunoassays. Increases in sample volume and antibody concentrations, along with changes in antibody selection and blocking reagents (to suppress background noise), are all commonly used. Three novel platforms that use different approaches to detect troponin are discussed later. Investigational High-sensitivity Assays
The Singulex cTnI assay is a sandwich immunoassay. Troponin is captured by antibodies conjugated onto paramagnetic particles, followed by washing and incubation with fluorescent labeled detection antibody. Extensive washes and the transfer of paramagnetic particles to a new plate reduce background caused by nonspecific binding of detection antibody. The sample is then eluted, dissociating the antibody binding, allowing buffer containing troponin and the detection antibody to be aspirated into the Erenna reader. The sample flows through a capillary, passing through a focused laser beam, which induces fluorescence in the antibody label. At low concentrations, the analyte is measured as a series of discrete pulses counted in 1-millisecond bins, representing the detection of an individual antibody, measured as a detected event (DE). With increasing concentration, pulses begin to overlap, requiring that the average photons per event (EP) and total photons (TP) measured per sample are also recorded. The measured DE, EP, and TP are fitted against 3 standard curves, whose weighting changes with analyte concentration to produce measured values across a wide measuring range.32
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Table 1 Analytical characteristics of cardiac troponin assays Commercially Available Assays Company/Platform(s)/Assay
LoB (ng/L)
99th % (ng/L)
%CV at 99th %
Epitopes Recognized by Antibodies
Abbott Architect
ALM,
Petr Jarolim,
MD, PhD*
KEYWORDS Cardiac markers Cardiac troponin High-sensitivity assay Biomarker Acute myocardial infarction Adverse event Risk prediction KEY POINTS This article discusses: The classification of cardiac troponin I and T assays according to their sensitivity. The requirement of the universal definition of myocardial infarction to establish the increase and/or decrease in cardiac troponin concentrations in patients and the 99th percentile of cardiac troponin concentrations in healthy individuals. Applications of high-sensitivity cardiac troponin assays for short-term and long-term prediction of adverse cardiovascular events.
INTRODUCTION
The development and ongoing implementation of the high-sensitivity cardiac troponin assays has generated considerable interest. Increased sensitivity offers opportunities for greatly improved diagnostics, but some clinicians are concerned about the reduced specificity of these assays. This article discusses the impact of the gradual implementation of high-sensitivity cardiac troponin assays on the clinical diagnostics of acute coronary syndrome (ACS), as well as short-term and long-term prognosis of adverse cardiovascular events. The structure and function of cardiac troponins are also reviewed.
Disclosure Statement: P. Jarolim received consulting income from T2 Biosystems and Quanterix, and research support from Abbott, AstraZeneca, Daiichi Sankyo, Merck, Roche Diagnostics, and Waters Technologies; M.J. Conrad received consulting income from Quanterix. Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Harvard Medical School, Boston, MA 02115, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med 34 (2014) 59–73 http://dx.doi.org/10.1016/j.cll.2013.11.008 labmed.theclinics.com 0272-2712/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
60
Conrad & Jarolim
STRUCTURE AND FUNCTION OF CARDIAC TROPONINS Components of the Cardiac Troponin Complex
Troponins are arranged in a heterotrimeric complex consisting of 3 troponin molecules, whose names are derived from their functions: calcium-binding troponin C (TnC; 18 kDa), inhibitory troponin I (TnI; 24 kDa), and tropomyosin-binding troponin T (TnT; 37 kDa). The complex attaches to the thin filaments of muscle and acts to regulate muscle contraction. The troponin isoforms expressed in muscle tissues differ based on the tissue’s role, with the cardiac myocyte uniquely expressing the cardiac TnI (cTnI) and cardiac troponin T (cTnT) isoforms. This tissue specificity has driven the use of cardiac troponins as biomarkers for cardiac injury. Although there is a so-called cardiac troponin C (cTnC), it is expressed in both cardiac and slow skeletal muscle.1 The troponin complex plays an essential role in regulating the excitation-contraction coupling in skeletal and cardiac muscle through calcium signaling. Without calcium bound by TnC, the TnI protein binds the heterotrimer closely to the thin filament. The binding of calcium by TnC causes a conformational change, exposing a hydrophobic section to which TnI preferentially binds. In doing so, the complex is able to swing away from the thin filament, allowing TnT to bind tropomyosin, and exposing actin binding sites that previously were covered by TnI. This process drives muscle contraction.1 Cardiac Troponin Genes
Three pairs of troponin genes are located adjacent to each other on chromosomes 1, 11, and 19. Cardiac troponins do not form a pair on the same chromosome. Instead, the cTnI gene, TNNI3, is located on chromosome 19, whereas the cTnT gene, TNNT2, is located on chromosome 1.1,2 Isoforms can be encoded by separate genes or created through alterative splicing.2,3 The troponins are generally well-conserved genes, and mutations in cTnI and cTnT have been implicated in the pathogenesis of several conditions, including hypertrophic cardiomyopathy.1,4 Cardiac Troponin Gene Expression
The expression of troponin differs significantly between the embryonic and adult hearts. Although cTnC is expressed consistently throughout life, slow skeletal TnI is expressed in the hearts of embryos along with some cTnI, transitioning after birth to cTnI alone by 9 months after birth.5,6 The process for cTnT is more complex, because a mix of TnT1 and TnT3 predominate in the embryo, shifting to TnT3 and TnT4 after birth.1 There is evidence of a tendency toward reverting to fetal expression patterns in the ailing heart, and there are some rare cases of cardiac troponin expression outside the heart, which complicates the overall picture.1,7 Translation and Posttranslational Modifications
Turnover of the three troponin proteins was found in rats to occur at different rates, perhaps because of the localization of the genes across separate chromosomes and because their half-lives range from 3 to 5 days.8,9 Replacement of the troponins seems to occur randomly along the thin filaments in differentiated adult rat cells, rather than in an ordered fashion, which implies that maintenance of these filaments is performed while maintaining functionality, allowing consistent cardiac activity.8 The action of cardiac troponins may be tuned through phosphorylation or cleavage, altering cardiac output potential.1,10 Troponin Release from Cardiac Myocytes
Most troponin is bound to thin filaments as part of the structural pool. A small portion is free in the cytoplasm as the cytoplasmic pool. The cytoplasmic pool is the likely
High-sensitivity Cardiac Troponin Assays
source of the initial increase in serum troponin after myocardial injury, with subsequent troponin being released from the degraded structural pool. The estimates for the size of the cytoplasmic pool differ widely, ranging from 3% to 8% of the total cellular troponin.11–13 The major forms of troponin released into circulation are cTnT and the cTnI-TnC complex. Additional forms found circulating in plasma are the cTnT-cTnITnC ternary complex and free cTnI.11,14 The mechanism of troponin release from cardiac myocytes, in the absence of acute injury, is not completely understood. Although the so-called troponin leak is frequently mentioned, there are no data explaining this term, and it is unlikely that the sizable troponin molecules are released into circulation from viable cardiac myocytes. Perhaps the only mechanism that would allow limited release of troponin and leave behind viable cardiac cells is the formation of exosomes containing small amounts of the free, cytoplasmic troponin. Formation of blebs in cardiac myocytes exposed to ischemia has been reported.15,16 In our opinion, the most likely mechanism leading to the presence of cardiac troponin in circulation is myocyte death occurring physiologically as part of the continuous renewal of cardiomyocytes. The process of cardiomyocyte renewal is generally accepted, although there are major discrepancies in the estimates of its rate. According to some investigators, the heart is replaced on average 11 to 15 times during a person’s lifetime,17 but according to other investigators, only 40% of the heart is replaced.18 After release from the myocyte, troponin is degraded, fragmented, and cleared. These processes are not fully understood, creating analytical challenges.16,19,20 CARDIAC TROPONIN ASSAYS History of Cardiac Troponin Immunoassays
The first cardiac-specific troponin I assay was described in 1987 by Cummins and colleagues,21 and the first commercial cTnI assay was brought to the market by Dade Behring for use on the Stratus I analyzer. Compared with this first investigational cTnI assay, current commercial troponin I assays are more than 1000 times more sensitive, with the sensitivity of the investigational assays an additional 10 to 100 times higher. The first cTnT assay was developed by Katus and colleagues22 in 1989. The initial limit of detection (LOD) was 500 ng/L. Again, sensitivity of the original assay is about 2 orders of magnitude lower than that of the current high-sensitivity TnT (hsTnT) assay, with a LOD of 3 ng/L. Standardization of Cardiac Troponin Immunoassays
Despite more than a decade of efforts to standardize cTnI assays from different manufacturers, only minor progress has been made. Fig. 1 shows the diverse combinations of capture and detecting antibodies for different cTnI assays, each with its own incubation conditions, heterophile blocking reagents, detection technologies, and standard materials, which illustrates why it is difficult to obtain identical numeric results for cTnI concentrations using immunoassays from different manufacturers. It is unlikely that standardization of cTnI assays will be accomplished soon.23 Standardization of the cTnT assay is not a major problem. Because of patent issues, the cTnT assay is only available from Roche Diagnostics, so the only inconvenience is the current coexistence of the less sensitive fourth-generation cTnT assay in the United States and the high-sensitivity hsTnT assay in most other countries. Nevertheless, although these two assays use the same monoclonal antibodies and should
61
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Conrad & Jarolim
Fig. 1. The cTnI molecule (amino acids 1–210), stable central region,20 and antibody binding sites (capture in gray, detection in black) for selected assays from Table 1.
theoretically produce almost identical results, correlation at the low end is not linear, producing higher numerical results in the high-sensitivity assay compared with the fourth-generation cTnT.24 Another complication when interpreting results of certain studies using high-sensitivity assays is the recently reported miscalibration issue,25–28 which has led to underestimation of cTnT concentrations at the low end and potentially invalidated conclusions of certain studies. However, recalculation of results greater than LOD is possible and may be performed by Roche Diagnostics. Although cTnI and cTnT should be released from damaged cardiomyocytes in equimolar amounts, cTnI and cTnT correlate poorly, a situation that is worsened when accounting for multiple cTnI assays. This effect may be caused by several mechanisms: different stability of cTnI and cTnT in the circulation, different clearance rates in different patients, different ratio of free cTnI and cTnT pools in the cytoplasm of the damaged myocytes, and so forth. What Defines a High-sensitivity Cardiac Troponin Assay?
The large increase in sensitivity of cTn assays is shown in Fig. 2, which plots the limits of detection and 99th percentiles for 5 categories of cTn assays. We call the oldest, category, which is no longer used, low-sensitivity assays. These assays only detected the largest increases of cTn, without detecting other pathologic, albeit less dramatic, increases. We prefer to call the assays currently available in the United States medium sensitivity assays, although they have been referred to as contemporary assays.29 These assays reliably detect cTn increases to more than the 99th percentile, but are able to quantitate cTn in only a fraction of healthy individuals. Conventional troponin assays have had a clear performance goal of measuring troponin with a 10% coefficient of variation (CV) at the 99th percentile of their reference population. As manufacturers have worked to increase the sensitivity of their assays, the definition of high-sensitivity in cTn assays has changed. The International Federation of Clinical Chemistry (IFCC) task force suggested in 2012 that in order to label a cardiac troponin assay as highly sensitive, cTn should be measurable in more than 50% of healthy subjects, and preferably in more than 95%.30 We suggest that an ideal high-sensitivity assay should quantitate troponin in 100% of a healthy reference population and would have a 10% CV at the 10th percentile for the same population. This level of performance would make it possible to consider personal reference ranges or small delta values over short time frames for use in emergency
High-sensitivity Cardiac Troponin Assays
Fig. 2. Sensitivity of cardiac troponin assays. The effect of increasing cTnI assay sensitivity relative to a healthy population and the measured 99th percentile for each assay along with 10% and 20% coefficient of variation (CV) limits.
care. More importantly, it is not clear that performance in excess of this standard would be valuable in the clinical setting. The performance of current troponin assays is summarized in Table 1. We reserve the term ultrasensitive for assays capable of quantitating cTn at levels less than the lowest cTn concentrations seen in healthy individuals. Additional sensitivity may be beneficial for novel applications of the cTn assays, such as measuring cTn levels during diagnostic procedures31 or using them for early detection of druginduced cardiac toxicity in experimental animal models. Assays with improved sensitivity, such as the Abbott hsTnI and Roche hsTnT assays, have generally been developed using a variety of standard steps taken to improve immunoassays. Increases in sample volume and antibody concentrations, along with changes in antibody selection and blocking reagents (to suppress background noise), are all commonly used. Three novel platforms that use different approaches to detect troponin are discussed later. Investigational High-sensitivity Assays
The Singulex cTnI assay is a sandwich immunoassay. Troponin is captured by antibodies conjugated onto paramagnetic particles, followed by washing and incubation with fluorescent labeled detection antibody. Extensive washes and the transfer of paramagnetic particles to a new plate reduce background caused by nonspecific binding of detection antibody. The sample is then eluted, dissociating the antibody binding, allowing buffer containing troponin and the detection antibody to be aspirated into the Erenna reader. The sample flows through a capillary, passing through a focused laser beam, which induces fluorescence in the antibody label. At low concentrations, the analyte is measured as a series of discrete pulses counted in 1-millisecond bins, representing the detection of an individual antibody, measured as a detected event (DE). With increasing concentration, pulses begin to overlap, requiring that the average photons per event (EP) and total photons (TP) measured per sample are also recorded. The measured DE, EP, and TP are fitted against 3 standard curves, whose weighting changes with analyte concentration to produce measured values across a wide measuring range.32
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Table 1 Analytical characteristics of cardiac troponin assays Commercially Available Assays Company/Platform(s)/Assay
LoB (ng/L)
99th % (ng/L)
%CV at 99th %
Epitopes Recognized by Antibodies
Abbott Architect
