Clinical Instrumentation (Immunoassay Analyzers) Daniel W. Chan Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, Maryland 2 1287
Immunoassay automation is one of the most exciting areas of research and development in the diagnostic industry. The clinical laboratory has strong interest in selecting and utilizing automated immunoassay analyzers. At the present time, the clinical laboratory is faced with increasing challenges, which include the shortage of qualified technologists,limited laboratory space, and shrinking resources, and external challenges, such as health care reform, managed care competition, cost compression, and increased regulation of the testing laboratory. In addition, the Clinical Laboratory Improvement Amendment of 1988 (CLIA ’88) has placed additional burden on the laboratory in terms of quality assurance, proficiency testing, and competency requirements. Despite these challenges,physicians have higher expectations for laboratory services. In order to meet these challenges successfully, the clinical laboratory has to become more efficient through the “reengineering” process. One solution is to increase automation of laboratory procedures and integrate these automated systems. Since most clinical laboratory procedures are labor-intensive,automation will reduce the dependency on the labor requirement. Furthermore, smaller clinical laboratories could perform a larger menu of tests “in-house”rather than sending to outside laboratories. With the availability of automated devices designed for point of care testing, laboratory tests may be relocated to “near-patient”. The last review by Haas (VI),especially Table 0-1, provided a comprehensive summary of automated immunoassay analyzers. Some of these analyzers just became available, for example, the Immuno 1and the Radius analyzers. The development and the availability of automated immunoassay analyzers for the clinical laboratory has taken longer than expected because of dficulties in both technical issues and computerization of these instrumentations. This review covers the last two years from October 1992 to October 1994. Some new instruments were introduced, for example, the AxSym analyzer by Abbott Laboratories; others were updated, for example, the ACS180 plus and the ES300al analyzers. Greater emphasis is being placed on the continuous access feature and the ability to handle primary blood drawing tube through direct sampling and barcode reading. These features minimize the handling of infectious specimens and errors in transferring specimen. Two concepts emerging as leading candidates for future improvement of automated immunoassay analyzers are homogeneous immunoassay and nanotechnology. The new approach for homogeneous immunoassay will allow both small and large analytes to be measured. Nanotechnology will miniaturize the automated devices, improve sensitivity and allow multiple analytes to be measured simultaneously. With reliable small analyzers, testing could be performed in the point of care setting. This review is based in part on the two books edited by myself, entitled Immunoassay Automation: A Practical Guide (U2)and Immunoassay Automation: A n Updated Guide to Systems (U3). Another recent book edited by Wild devoted one-sjxth of the book on automated immunoassay systems (U4).Readers are referred to these three publications for more detailed information on individual automated systems.
AUTOMATED IMMUNOASSAY SYSTEMS Homogeneous Immunoassay Systems. Homogenous immunoassay requires no physical separation of bound and unbound antigen. The major advantage is the ability to adapt reagent to the existing clinical chemistry analyzer. For example, the enzyme multiplied immunoassay technique (EMIT) by Syva Co. could be used on the Boehringer Mannheim Corp. (BMC)/Hitachi analyzer. The automated homogenous immunoassay systems use small sample size and low reagent volume and provide fast turnaround time. The calibration curve is stable for at least several days. This allows the laboratory to perform tests at any time without having to recalibrate the system. Efficiency is enhanced by saving technical time, quality control, and reagent expenses. Most homogenous immunoassays take advantage of the size difference between unbound antigen (small) and antigen-bound antibody complex (large). The differences in the sizes may limit the changes in signal detection. This will in turn limit the dynamic ranges of the assay and, to a certain extent, the sensitivity as well. Since there is no separation of the patient sample from the final signal detection, the specificity may be compromised. Interferences from the patient‘s sample may cause high background signal or compete with the binding site. Some tests require sample pretreatment to eliminate interferences. For example, digoxin assay requires an acid precipitation [TDx analyzer (Us) by Abbott Labs] before analysis. In general, small analytes such as drugs and thyroid and steroid hormones, which are present in relatively high concentration, could use the homogenous format. On the other hand, large molecules such as protein antigens would be difficult to measure by the homogeneous immunoassay due to poor sensitivity and unacceptable imprecision. (a) Open System. An open system consists of a generalpurpose instrument designed to perform chemistry tests. An immunoassay reagent could be adapted to the instrument if it shares the same sample delivery and detection device and requires no physical separation of unbound from bound antigen (homogeneous). For example, the BMC/Hitachi analyzers 747 and 911 are designed to perform routine chemistry tests such as glucose, cholesterol, and alkaline phosphatase. The EMIT reagent could be adapted to these instruments because they use the same pipeting device and the spectrophotometric detection step. Because immunoassay may require more than one reagent or reaction step than the simpler chemistry test, not every general chemistry instrument can be used for homogeneous immunoassay. For example, the “cloned enzyme-donor immunoassay” (CEDIA) reagent for vitamin B12 and folate uses reagent components that require four reagent addition steps. The Hitachi 704 analyzer is not designed to handle these many steps, whereas the Hitachi 911 analyzer is. The open systems do have the advantage of the user‘s choice of reagent and potential competitive edge of more than one reagent. With the introduction of CLIA ’88 and the U.S. Food and Drug Administration (FDA) approval process, open systems will have to specify the reagent and the instrument combination in the FDA approval process. Examples of these systems are shown in Table 1. (b) Closed System. A closed system is one that uses a specific reagent designed for a particular instrument. Generally, AnalyticalChernistry, Vol. 67, No. 12, June 15, 1995
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Table 1. Homogeneous Immunoassay Systems instrument Hitachi 747, 9 11 Olympus AU5000 Miles Chem 1 Roche CobaslMira Beckman Array Abbott TDX, ADX Roche Cobas FARA DuPont ACA Miles Immuno 1 IGEN - Origen Sienna Biotech BMC - OIB
reagenta
ref
Open Systems CEDIA, EMIT EMIT EMIT EMIT nephelometric Closed Systems FPIA FPIA PETINIA turbidity Combined Systems LIA-ECL Copalis-flow cytometry FIA-OIB
u5 U6 u7 U8
u9 u10 u11
Reagents: CEDIA, cloned enzyme-donor immunoassay; EIA, enzyme immunoassay; EMIT, enzyme multiplied immunoassay technique; FIA, fluorescent immunoassay; FPIA, fluorescent polarization immunoassay; LIA, luminescent immunoassay; PETINIA, particle-enhanced turbidimetric inhibition immunoassay. the same company produces both the instrument and reagent, although there are few exceptions. For example, the popular TDx analyzer made by Abbott Diagnostics (Us)uses fluorescent polarization immunoassay (FPIA) reagents made by Abbott. Because there are so many TDx analyzers for the testing of therapeutic drugs, FPIA made by other companies became available. The Roche Cobas FARA I1 analyzer also uses FPIA (US).The DuPont ACA analyzer uses the particle-enhanced turbidimetric inhibition immunoassay (PETINIA) (U7).The Miles Immuno 1analyzer (US) uses latex agglutination assay to measure therapeutic drugs and thyroxine. The principle of the Immuno 1 homogeneous immunoassay is based on the competition between the specifk analyte and the analyte-Ficoll conjugate with antibodycoated latex particles. The agglutination rate is monitored by the turbidity at 600 nm. The advantage of a closed system is that the overall quality of the performance can be better controlled by the manufacturer. The disadvantage is usually the higher price of the reagent. Examples of closed systems are also shown in Table 1. (c) Combined Homogeneous Immunoassay System. The combined homogeneous immunoassay system uses either “open” or “closed” reagents and has the ability to measure both small and large molecules. Most of these systems are available for research use only. They incorporate a unique approach so that both large and small molecules can be measured in a homogeneous format. In addition to immunoassay, the electrochemiluminescence (ECL) technology has been applied to the detection of nucleic acid, for example, the IGEN system (US).The Copalis system could be used to detect markers on the cell surface in addition to the coupled particles for immunoassay (U10).It uses a flow cytometry approach. An instrument employing an optical immunobiosensor (OIB), which uses either conventional competitive or immunometric assay with fluorescent conjugate, (U11)was developed by BMC. The fluorescence produced by the evanescent wave generated by the molded polystyrene optical fiber is detected by an immunosensor. This allows a short reaction time of less than 5 min while achieving similar sensitivity as conventional immunoassay. Heterogeneous Immunoassay System. The heterogenous immunoassay is more versatile. It can measure both small and 520R
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Table 2. Heterogeneous Immunoassay Systems company
instrument
reagenta
separationb testC
Kodak Hybritech Abbott
Semiautomated Systems Amerlite LIA cw PhotonQA EIA CB Commander CB EIA
Abbott Baxter
IMx Stratus I1
BMC BioRad BioMerieux Syva Abbott BD Behring Biotrol Ciba DPC DuPont Fujirebio Miles Roche Sanyko Sanofi Serono Tosoh Wallac
Batch-Automated Systems FIA PF FIA CF
H T I
ref U12 U13
H,T H,D
U14 U15
Selective Automated Systems ES-300al EIA CT Radius EIA CW VIDAS FIA CW Vista FIA MP
H,T H H,I H
U16 U17 U18 U19
Continuous-Access Automated AxSym FIA and FPIA Affinity EIA Opus Magnum FIA System 7000 EIA ACS-180 PIUS LIA Immulite LIA ACA Plus EIA Lumipulse 1200 LIA Immuno 1 EIA Cobas Core EIA Luminomaster LIA Access LIA SR- 1 EIA AIA- 1200DX FIA AutoDELFIA tFIA
A H A H H,T H A H,I,T A H,T H. T H,I H H,T H,T
U20 U21 U22 U23 U24 U25 U26 U27 US U28 U29 U30 U31 U32 U33
Systems PF CT CFMF MP MP CB MP MP MP/TB CB CT MP MP MP
cw
Reagents: EIA, enzyme immunoassay; FIA, fluorescent immunoassay; FPIA, fluorescent polarization immunoassay; LIA, luminescent immunoassay; tFIA, time-resolved immunoassay. Separation: CB, coated bead; CF, coated filter paper; CT, coated tube; CW, coated well; MF, multilayer film; MP,magnetic particle; PF, particle filter; TB, turbidimetric. Test: D, drug; H, hormone; I, infectious disease; T, tumor marker; A, all. large analytes. With a physical separation step, it eliminates most interfering substances present in the patient’s sample before quantification. The separation step together with the potential of using a larger sample size will improve the sensitivity. The immunometric assay tends to have a broader dynamic range of the standard curve. The peptide hormone and tumor marker are ideally measured by immunometric assay, for example, human chorionic gonadotropin @CG) and prostate-specific antigen (PSA). The disadvantages of heterogenous immunoassay are that it is more labor-intensive and time-consuming and requires a dedicated immunoassay analyzer. (a) Semiautomated Immunoassay System. An automated instrument can be built on multiple blocks. These building blocks may be linked by computer program or mechanically attached together. In most semiautomated systems, these blocks function separately: for example, the pipeting of reagent, the incubation of the reaction mixture, the bound/free separation by washing the solid phase, the signal detection, and the data management steps. These systems operate in a batch concept, Le., testing of all samples for the same analyte. Most fully automated heterogenous immunoassay systems are relatively slow, with throughput between 30 and 150 tests/h. Therefore, a high-volume testing laboratory may benefit from using a semiautomated system that takes care of the most labor-intensive steps, leaving the less timeconsuming steps for the technologist. Examples are the Kodak Amerlite (UIZ), Hybritech Photon QA (U13), and Abbott Commander analyzers (Table 2). (b) Fully Automated Immunoassay System. Fully automated immunoassay systems link all the separate components of
the semiautomated system and allow the testing to be completed from the sample addition to result reporting. Depending on the ability of the system to select sample for analysis on demand, the fully automated system can be further subdivided into batch, selective, and continuous-access systems. The batch immunoassay systems have been the primary working systems in the clinical laboratory for the last few years. Examples are the Abbott IMx (U14)and the Baxter Stratus I1 (U15)analyzers (Table 2). These systems are small in size and relatively slow in throughput. For a large laboratory, several of these analyzers are needed to handle the workload. The advantage is the redundancy of multiple analyzers. The disadvantages are the need for more personnel time and matching results from different instruments. They are being replaced by the random access systems. The selective system is similar to the batch system; however, the selective system has the ability to perform more than one test for a given specimen. Once the reaction starts for a particular batch of specimens, no more specimens can be added until the completion of the testing. It is useful for laboratories with a relatively large test volume and for routine tests with longer Bioturnaround time. Examples include the BMC ES300al (U16), Rad Radius (U17), BioMerieux VIDAS (U18), and the Syva vista (U19)analyzers (Table 2). This type of automation cannot be used for emergency testing. Because of their inability to test continuously, selective systems are also being replaced with the truly continuous, random-access systems. The continuous-access system will be the standard of automated immunoassay systems in the next few years. These systems allow continuous access of the testing process by adding additional specimen and reagent. The throughput varies from 30 to 150 tests/h. Some of the systems listed in Table 2 are new, for example, the Abbott AxSym (UZO), which essentially consolidates the successful TDx, IMx, and ADx into one automated system. Several systems including the Abbott AxSym, Miles Immuno 1 (US) and DuPont ACA plus (UZ6)combine homogeneous and heterogeneous assays into one single system. This approach allows faster throughput for small analytes, for example, drugs. Some systems are updated with additional features like automatic sample loading and improved throughput, for example, the Ciba ACS18Oplus (UZ4), the Tosoh AIA-12OODX (U32), and the BMC ES300al (U16).The Sanofi Access (U3O), Ciba ACS 18Oplus, and DPC Immulite (U25)systems use chemiluminescence to improve sensitivity. The autoDELFIA (U33) uses timeresolved fluorescenceto improve specificity. Other systems have become more automated or increased the throughput, for example, the Behring Opus became the Magnum (UZZ)and the DELFIA became autoDELFLA, Two automated systems made by Japanese companies are not yet available in United States, the Lumipulse 1200 by Fujirebio (U27) and the Luminomaster by Sankyo (U29). FEATURES OF AUTOMATED IMMUNOASSAY SYSTEM
Reagent. In the development of an immunoassay, the competitive approach conserves the use of antibody in the assay since the antibody concentration is limited. Traditional RIA is based on the principle of competitive protein binding. The radioactivelabeled antigen competes with the unlabeled antigen for a limited amount of binding sites on the antibody. “Sensitivity”as defined by the minimum detectable amount is affected by the affinity
constant of the antibody, the nonspecific binding, the specific activity of the labeled antigen, and the experimental error in the measurement of bound and unbound antigen. Immunometric assay could be optimized for better sensitivity than the competitive immunoassay. The maximal sensitivity can be achieved with a large concentration of labeled antibody with high specific activity, low amount of nonspecific binding by the labeled antibody, high af6nity constant of the labeled antibody, and small experimental errors in measuring the bound labeled antibody. Most automated immunoassay systems employ both competitive and immunometric assays. The decision on which format to use will depend on the size of the analyte. The choice for small analytes is the competitive immunoassay, while for large analytes it is the immunometric assay. Immunometricassay provides both sensitivity and speciiicity needed for peptide hormones, for example, parathyroid hormone (PTH) and adrenocorticotropic hormone (ACTH). The specificity of measuring the intact molecule of PTH could exclude the FTH c-terminal fragments which accumulate in renal disease. Sample Management. The sample management system is becoming increasingly important as the concern of infectious specimens rises. A random-access device is preferred since test requests vary with each individual patient. Furthermore, random access will allow the laboratory to perform testing continuously and eliminate the batching and scheduling of tests. A sample management system could include sample processing and introduction to the instrument. Positive identification,e.g., barcode label, should be applied at the blood collection step. The primary blood drawing tube could be centrifuged and transferred to the testing step. The concept of centrifugation along the axis of the tube will allow direct sampling through the top of the tube. Another approach is the use of an automating cap removal device. Either approach will allow the sample management system to be fully automated. The sample introduction system should be designed to minimize carry-over. Carry-over is not a major problem for general chemistries since the physiological ranges of most analytes are rather limited. However, carry-over could be a significant problem for hormones and tumor markers. It is not uncommon to have a 105-folddifference in the values of tumor markers. An ideal target for carry-over is less than 1 part per million. To minimize carryover, the design of the sampler such as the shape, size, and materials is important. Adding a washing step in between each sampling may help reduce cany-over. Signal Detection. The type of signal detection system is determined by the signal or the label of the reagent. The choice should be based on technical performance and economic considerations. A system should be able to achieve the sensitivity of most clinically important analytes with acceptable precision, be easy to build, and be relatively inexpensive, common, and easy to troubleshoot. Three types of detection systems that fit these criteria have been used in most automated systems. Spectrophotometry is probably the most popular detector. Enzyme immunoassay (EIA) could be homogenous or heterogenous. In the heterogenous assay, the two most frequently used enzymes are alkaline phosphatase and peroxidase. Fluorometry is widely used for both homogenous and heterogenous immunoassay. Some systems use enzymes to convert a substrate to a fluorescent product, while others use both Analytical Chemistry, Vol. 67,
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spectrophotometry and fluorometry in the same system. In theory, fluorometry is capable of detecting as little as mol of a compound, while spectrophotometry can only detect lo-* mol. In practice, the sensitivity is much reduced due to the background noise from the endogenous fluorophore, e.g., bilirubin, protein, and lipids. Time-resolved fluorescence technique such as the autoDELFIA system by Wallac (U33) may somewhat reduce this problem. Luminometry is gaining popularity rather quickly. Luminescence immunoassay (LIA) has the potential of achieving the highest sensitivity. Most LIAS are heterogeneous assays. Taking advantages of the inherent sensitivity, Nichols Diagnostics developed an ultrasensitive thyrotropin (TSH) assay which is capable of measuring TSH to 0.005 mIU/L. Data Management. The Data Management System is the command center of the laboratory. In order to effectively manage automation, the data management system should control as many steps in the total testing process as defined earlier. The system should be designed to be user-friendly and allow a technologist to perform the crucial daily functions efficiently. Diagnostics of instrument malfunction are important for troubleshooting purposes. Troubleshooting can be performed by the operator or with remote diagnostics through modem or satellite connection to the manufacturer. Modem instruments should contain built-in sensors for the proper operation of the system. Examples are “detector of short sample” by the pipetor. Continuous monitoring and self-adjusting may be necessary for a truly “walk-away” automation. A real-time, on-line quality control (QC) system allows the technologist to make a quick decision on the acceptability of the laboratory result. In this verification step, an “exception” list of results could be generated for further investigation. Results not in the exception list will be allowed to pass through to the reporting step. The rules for the exception list should be userdefined. Sample and patient identification should be done by a barcode device with a unique identifying label generated as early as possible in the history of the sample. This label will provide positive identification throughout the entire testing process. It should contain all the testing information and provide a link to the patient identification. An automated system should be able to communicate with the host computer with a bidirectional interface. A buffer to store laboratory data will be important in the event that the host computer is “down”. Other management functions will be useful for a laboratory to evaluate the testing data, workload recording, turnaround time, productivity, quality assurance, and efficiency of the operation. However, these management functions are less critical and should not interfere with the daily operating routines. Jimitations of Automation. One of the limitations of automation is the need for capital equipment acquisition. Most fully automated systems use dedicated reagents. The closed system “locks in” the laboratory to use all the reagents from the same manufacturer, even though they may not have the same quality. The choice of tests is also limited by that particular system. The commitment for an automated system is usually 3-5 years. While the quality of reagent may change, the instrument will also be obsolete. The throughput of most automated systems using a heterogenous format is between 30 and 150 tests/h. All instruments S22R
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require maintenance and service. The total dependency of an automated system means that the entire immunoassay system may be shut down. The limited throughput as well as the reliability issue causes many laboratories to acquire more than one system. Finally, one should not overlook the human factor. Most instruments are advertised as “walk-away”. However, as technologists walk away from the instrument, they are concerned about the outcome of the testing-what if the instrument malfunctions and none of the results are acceptable? Summary of Key Features of Automated Immunoassay Systems. The key features of automated immunoassay systems are summarized in Table 3. The type of automation could be selective or continuous access. The availability of the number of analytes varies from country to country because of the specific regulation and approval process. For example, the FDA approval process in the United States can be lengthy, depending on the type of medical device. Tests for tumor markers and infectious disease agents require premarket approval (PMA) application. The availability of these tests for clinical use in United States tends to be later than other countries. The type of analyte could include hormone, drug, tumor marker, and infectious agent. Few systems have the complete menu. Most systems start with the measurement of hormones and then either tumor markers or infectious agents are added. Very few systems have a complete menu of drug assays for both therapeutic drug and abused drugs. Since most drugs could be measured by a general chemistry analyzer, these dedicated immunoassay analyzers offer other analytes to complement the drug analyzer. The one exception is digoxin. Many systems include digoxin because digoxin is present in lower concentration than the other TDM drugs and the need of providing “stat” turnaround time. The assay formats include homogeneous, heterogeneous, competitive binding, immunometric (sandwich),label (acridinium ester, enzyme, fluorescent compound, latex particles), and signal (spectrophotometric, fluorometric, time-resolved fluorescent, luminescent, turbidimetric). The separation step could be coated bead, filter paper, tube, well, multiple-layer film, magnetic particle, or particle filter. In the case of homogeneous immunoassay, there is no physical separation step. The number of assays available on the system is important for the continuous-access operation. The sampling aspect includes the tray capacity for samples which will determine the walk-away ability. The sampling from the primary blood drawing tube with barcode reading capability will eliminate the manual sample handling step. The capability to add a stat sample without interruption of the instrument operation will facilitate the smooth operation of the laboratory. The throughput of the system should be examined in terms of the incubation time, the time required for the first result and subsequent results. The maximum throughput is usually difficult to achieve. The real throughput is complicated and usually depends on a particular test mix. Finally, the calibration curve stability will be compared with the frequency of calibration. Some systems are calibrated for each lot of reagent. On a daily basis, one or two calibrators are used to adjust the curve. FUTURE TRENDS
The design of the future automated immunoassay system will depend upon the needs of the testing sites, quality expectations, and technological advances.
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The future clinical laboratory will be located where the patients are. Outpatient testing could be performed at testing centers or at the patient’s home. It depends on the need of turnaround time, the complexity of the test, and the cost. I believe that the turnaround time issue will be less critical in the future as more automation will include preanalytical variables such as order entry, sample collection, transportation, processing, and result reporting. At the present time, such preanalytical variables often cause significant delay in the testing process. For in-patients, a hospital laboratory needs a system with a large menu and continuous access to different samples and tests. A commercial laboratory needs an automated system with higher throughput since most of the testing is routine in nature. The continuous-access feature is less critical. I believe more centralization of laboratory testing will occur to improve efficiency. Therefore, the high-throughput instrument will be in demand. System integration will be the next level of automation. Since an individual system may not fukill all the needs of a particular laboratory, multiple systems of the same or different type could be linked together with a common sample processor. The data generated by the different instruments could be reported by a common data management system. Furthermore, a totally integrated immunoassay system would be able to perform all the steps in the total testing process. Technological advances in immunoassay automation will result in miniaturized systems with better sensitivity, less interference, more consistency, and faster testing time. Designer antibodies with higher affinity and specificity could be used to improve sensitivity and analyte selectivity. Labels could be chosen to have higher signal for quantitation. Homogeneous immunoassay will facilitate sample handling and shorter reaction time, for example, the BMC system using an optical fiber evanescent wave fluoroimmunosensor. Multiple analytes could also be handled simultaneously using different labels, for example, the time-resolved fluorescent system (autoDELFIA). The other approach is the use of different sizes of particles, for example, the Copalis system. The laser detector of the flow cytometer could produce signals at different positions based on the size of the particle. Finally, an automated immunoassay system should be designed to meet the clinical needs and expectations of the user. It should include as many steps as possible in the total testing process. A system composed of individual modules may be the best approach. The module may be able to perform a group of tests suitable for a unique clinical setting, such as an emergency room, critical care unit, or outpatient clinic, for a specific medical discipline. Clinical settings would be the determining factor of the test menu on a particular system rather than the traditional laboratory disciplines of chemistry, microbiology, and hematology. Such modular systems would be most suitable for the changing needs of the clinical laboratory testing in the 1990s and beyond. Daniel W. Chan, Ph.D., DABCC, is the Director of the Clinical Chemist Division of the Johns Hopkins Hospital a n d h o d a t e Professor of Pathoxgy and Oncology at the School of Medicine, Johns Hopkins University. Dr. Chan received his B.A. in biology from Universit of Ore on and his Ph.D. in biochemist from the State Uni,ve@ty o f 8 e w Yorf at Buffalo. After completion oj? Postdoctoral training an Clznacal Chemist at the Erie County Laboratones in Buffalo,hejozned thefaculty of the Joxns Hopkans University. Dr. Chan is on the Board of Editors of Clinical Chemistly and the Journal of Clinical Immunoassay. His current research interests include tumor markers, prostate and breast cancer, endocrine assays, and immunoassay automatjon. Dr. Chan is the editor of three books and has published over 80 articles.
LITERATURE CITED (Ul) Haas, R. G. Anal. Chem. 1993, 65, 444R-449R. 524R
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Chan, D. W., Ed. Immunoassay Automation: A Practical Guide; Academic: San Diego, CA, 1992; pp 1-367. Chan, D. W., Ed. Immunoassay Automation: A n Updated Guide to Systems; Academic: San Diego, CA, in press. Wild, D., Ed. The Immunoassay Handbook; Stockton: New York, 1994; pp 137-239. Wong, S. H. TDx Systems. In Immunoassay Automation: A Practical Guide: Chan D. W.. Ed.: Academic: San Dierro. - CA, 1992; Chapter 23. Goldsmith, B. M. Cobas Fara I1 Anal zer. In Immunoassay W.. . Ed.; Academic: Automation: A Practical Guide: Chan. ?I San Diego, CA, 1992; Chapter 12. Litchfield, W.; Crai A R., Fre , W. A.; Leflar, C. C.; Looney, C. E.: Luddv. M. C%n. Chem. l984, 30, 1489-1493. Levine, J.; Ehresman, D. J. Immuno 1Automated Immunoassay System. In Immunoassa Automation: A n Updated Guide to Systems; Chan, D. W., E J ; Academic: San Diego, CA, in press. Blackbum, G. F.; Shah, H. P.; Kenten, J. H.; Leland, J.; Kamin, R. A.; Link, J.; et al. Clin. Chem. 1991, 37, 1534-1539. Bodner, .A. J.; Britz J. Copalis s stem. In Immunoassay Automatzon: A n Updated Guide to &stems; Chan D. W., Ed.; Academic: San Diego, CA, in press. Mahoney, W.; Lin, J. N.; Brier, R. A; Luderer, A. Real-time immunodiagnostics employin optical immunobiosensor. In Immunoassay Automation: Ankpdated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, CA, in press. Faix, J. D. Amerlite immunoassa system. In Immunoassay Automation: A Practical Guide; Cgan, D. W., Ed.; Academic: San Diego, CA, 1992; pp 117-127. Frye, R. F. The Photon-ERA immunoassay analyzer. In Immunoas!ay Automation: A Practical Guide; Chan D. W., Ed.; Academic: San Diego, CA, 1992; pp 269-292. Chou, P. P. IMx system. In Immunoassay Automation: A Practical Guide; Chan D. W., Ed.; Academic: San Diego, 1992; pp 203-219. Kahn, S.E.; Bermes, E. W. Stratus I1 immunoassay system. In Immunoassay Automation: A Practical Guide; Chan, D. W., Ed.; Academic: San Diego, 1992; pp 293-316. Sagona, M. A,; Collinsworth, W. E.; Gadsden, R. H. ES300 immunoassa system In Immunoassay Automation: A Practical Guide; d a n , D. W., Ed.; Academic: San Diego, 1992; pp 191-202. Russel, J.; Edwards R. Radius Immunoassay System. In Immunoassay Automation: An Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, in press. Ng, R. VIDAS System. In Immunoassa Automation: A n Ubdated Guide to Systems; Chan, D. W., dd.; Academic: San Diego, in press. Li, T. M. The Vista Immunoassa System. In Immunoassay Automation: A Practical Guide; &an, D. W., Ed.; Academic: San Diego, 1992; pp 343-349. Painter, P. The AxSym system. In Immunoassa Automation: A n Ubdated Guide to Systems; Chan, D. W., Ed.; Lademic: San Diego, in press. Chan, D. W.; Kelley, C. Aftinity immunoassay system. In Immunoassay Automation: A Practical Guide; Chan, D. W., Ed.; Academic: San Diego, 1992; pp 83-94. Shoemaker, B.; Velazquez, F. R. The Opus Magnum system. In Immunoassay Automation: A n Updated Guide to Systems. Chan, D. W., Ed.; Academic: San Diego, in press. Dellamonica, C.; Frier, C. J. Clin. Immunoassay, 1992, 15, 242-245. 1 Nee, G. The Ciba Coming ACS 180 automated immunoassay system. In Immunoassa Automation: A n Updated Guide to Academic: San Diego, in press. Systems; Chan, D. W., 1 Witherspoon, L. The DPC Immulite automated immunoassay system. In Immunoassa Automatzon: A n Updated Guide to Academic: San Diego, in press. Systems; Chan, D. W., (U26) Vaid a, H. C,; Zuk, P. J.; Ballas, R. A. ACA plus accessory for the .&A discrete clinical analyzer. In Immunoassay Automation: A n Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, in press. (U27) Okada, M.; Ashihara, Y.;Sakurabayashi, Y.; ,KO amaishi, Y. Nippon Rinsho Kagakkai Shzzkoku Shibu Kazshz 1 J 9 3 , 1 0 , 8 5 -
d.;
4.;
90.
oJ28) Huber, P. R. Cobas Core Immunoassay System. In Immunoassay Automation: A n Updated Guide to Systems; Chan, D. W., Ed.; Academic: San Diego, in press. (U29) Chujo, A. Nippon Rinsho Kagakkai Shiikoku Shibu Kaishi 1993, 10, 77-83. (U30) Guitard, M. The Access immunoassa system. In Immunoassay Automatzon: A n Updated Guide to &stems; Chan, D. W., Ed.; Academic: San Diego, in press. (U31) Demers, L. M. SR1 Immunoassa system. In Immunoassay Automation: A Practical Guide. &an, D. W., Ed.; Academic: San Diego, 1992; pp 277-292. (U32) Chan, D. W. AIA-1200 Immunoassay System. In Immunoassay Automation: A Practical Guide; Chan, D. W., Ed.; Academic: San Diego, 1992; pp 95-115. (U33) Gudmundsson, T. V.; Olafsdottir, E. AutoDELFIA system. In Immunoassay Automation: A n Updated Guide to Systems. Chan, D. W., Ed.; Academic: San Diego, in press. A19500072
