An Evaluation of the Roche Cobas c 111

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1 An Evaluation of the Roche Cobas c 111 James L. Bowling, PhD, DABCC, Alex Katayev, MD (Laboratory Corporation of America, Department of Science and Technology, Elon, NC) DOI: /LM6T8D1LKQXVNCAC Submitted Revision Received Accepted Abstract Background: The cobas c 111, a new low volume bench-top analyzer from Roche Diagnostics (Indianapolis, IN), was evaluated to determine whether the operational and performance characteristics of the system would make it a good fit for the physicians office laboratories and hospital stat labs in the Laboratory Corporation of America (LabCorp) network. Methods: Twenty-five frequently ordered analytes were evaluated relative to the published specifications of the cobas c 111. Additionally correlation studies, using patient serum samples, were used to determine interinstrument comparability between 2 cobas c 111 instruments and accuracy relative to the standardized assays at LabCorp. Results: Precision, linearity, method comparison to another large Roche system, inter-instrument comparability, potential carryover, and time to result studies met or exceeded expectations. Additionally, sigma metrics analyses graded the overall performance of this analyzer as world class. Conclusions: The analytical performance, compact size, intuitive operation along with the expected low maintenance and reliability make the cobas c 111 a good fit for the intended small laboratory niche environment at LabCorp. Keywords: chemistry analyzer, bench-top, small lab, stat lab The Laboratory Corporation of America (LabCorp) evaluated the cobas c 111 chemistry analyzer for placement in physicians office laboratories and hospital stat labs where it is the potential replacement for the Roche COBAS Mira (Roche Diagnostics, Indianapolis, IN). The cobas c 111 is a bench-top system with a small footprint suitable for low volume laboratories with limited floor space. The comprehensive test menu and easy integration of stat samples support testing of specialized assays, selected clinical panels, and rapid turnaround critical care markers. The intuitive user interface, barcode reader for samples, reagents and applications, and host connectivity option make the system very attractive in situations where operators may have minimal supervision and moderate skill sets. Additionally, the cobas c 111 uses the same bulk reagents as larger Roche systems currently used by LabCorp. This allows standardization of results across the LabCorp network or any other vertically integrated health care system that also selects the larger Roche platforms in their core laboratories. The objective is to provide consistent patient results with the same reference ranges throughout the network regardless of the point of service. Corresponding Author James L. Bowling, PhD, DABCC bowlinj@labcorp.com Abbreviations LabCorp, Laboratory Corporation of America; HIPAA, Health Insurance Portability and Accountability Act; IRB, Institutional Review Board; ALB2, albumin; ALP2S, alkaline phosphatase; ALTL, alanine aminotransferase; AMYL2, amylase; ASTL, aspartate aminotransferase; DBIL, direct bilirubin; BILTS, total bilirubin; CA, calcium; CHO2A, total cholesterol; CKL, creatine kinase; CL-I, chloride; CO2-L, bicarbonate; CRE2, creatinine; GGTS2, gamma glutamyl transferase; GLU2, glucose; HDLC3, high density lipoprotein; LIP, lipase; MG, magnesium; PHOS2, phosphate; K-I, potassium; NA-I, sodium; TP2M, total protein; TRIGL, triglyceride; UREAL, urea; UA2, uric acid; CVs, coefficients of variation; SD, standard deviation; GLU, glucose; K, potassium; TEa, total allowable error Materials and Methods All reagents, calibrators, and controls were FDA approved and used according to the manufacturers recommendations on the appropriate system. Linearity was performed using Validate linearity sets (Maine Standards, Windham, ME), which are US FDA cleared for use as calibration verification/linearity materials. They are available as a liquid; 5 6 bottle sets from Maine Standards. Precision studies used 2 levels of unassayed chemistry controls, Liquichek (Bio-Rad Laboratories, Irvine, CA). Sample Collection: Analyses were performed using fresh, de-identified spent serum samples used in accordance with the Health Insurance Portability and Accountability Act (HIPAA) and Institutional Review Board (IRB) policies in place at LabCorp. Statistical Analyses: Calculations of statistical values were performed using EP Evaluator Release 7 (David G. Rhoads Associates, Kennett Square, PA). Systems: The cobas c 111 bench-top system is part of the cobas family of analyzers from Roche Diagnostics. Method comparisons for all analytes were performed against the Roche/Hitachi MODULAR ANALYTICS P 398 LABMEDICINE Volume 41 Number 7 July 2010 labmedicine.com

2 Module system, also from Roche Diagnostics. Both instruments were operated as specified in Roche s operating manuals, using Roche reagents, standards, and controls as specified in the respective package inserts. Results The cobas c 111 test menu evaluation included the following 25 analytes listed with the Roche kit designation UNCLEAR: albumin (ALB2), alkaline phosphatase (ALP2S), alanine aminotransferase (ALTL), amylase (AMYL2), aspartate aminotransferase (ASTL), direct bilirubin (DBIL), total bilirubin (BILTS), calcium (CA), total cholesterol (CHO2A), creatine kinase (CKL), chloride (CL-I), bicarbonate (CO2-L), creatinine (CRE2), gamma glutamyl transferase (GGTS2), glucose (GLU2), high density lipoprotein (HDLC3), lipase (LIP), magnesium (MG), phosphate (PHOS2), potassium (K-I), sodium (NA-I), total protein (TP2M), triglyceride (TRIGL), urea (UREAL), and uric acid (UA2). The system uses the same calibrators, controls, and reagents available on the larger Roche platforms and performance met or exceeded comparative expectations. 1 Within run precision using 2 levels of Bio-Rad Laboratories Liquichek Unassayed Chemistry Controls and between day precision using Roche Diagnostics PreciNorm and PreciPath controls are described in Table 1. Initial inspection of the precision data shows some between run coefficients of variation (CVs) that are unexpectedly less than the within run CV. This divergence is primarily true for low concentrations of ALT, BILT, CO2, HDL, LIP, MG, and UA, is related to the use of different control material, and should not distract from additional review. Intra-assay CVs were largely <3.1% except for the BILTS low control, which was 5.6% at a level of 0.87 mg/dl. However, the BILTS inter-assay precision at a level of 1.0 mg/dl was 0.0%. Interassay precision was performed by running each control level twice per day over 5 days and included 2 to 3 calibrations per analyte. All inter-assay CVs were <2%, except for CO2 and DBIL, which were 3.4% and 4.2% respectively. The effect this large CV has on the DBIL assay performance is demonstrated by the poor performance grade (Sigma 2.36) assigned by the Sigma metric data presented in Table 5. Linearity (Table 2) was performed with ready-to-use 5-level linearity sets from Maine Standards that are loaded at 100% and 75%, 50%, 25%, and 12.5% of the high sample. Also included is a base matrix 0. Each level was analyzed in triplicate, and the mean value was compared to the expected value using regression analyses. Due to the concentrations in the sample sets, some analytes were not challenged up to the limits of their measuring range; however others were challenged above the manufacturer s stated claim, and all analytes showed linear recovery as evidenced by the slope and intercept values. Table 3 lists the linear regression slopes, intercepts, and correlation coefficients for all analytes comparing the recoveries on the cobas c 111 to the Roche/Hitachi MODULAR ANALYTICS P Module system. Analyte-specific sample sets were picked to challenge the measuring range. Except for CA, CL, and DBIL all methods showed acceptable comparative recovery. Both CA and CL show the effects of correlation data generated from specimens from a narrow distribution of values relatively to the expected 0 intercept. The CA slope of is fully compensated by the intercept as results approach 10.0 mg/dl. Likewise Table 1_Precision Test Within-Run Precision Between-Run Precision Test Test Units Mean %CV Mean %CV ALB g/dl ALP U/L ALT U/L AMY U/L AST U/L DBI mg/dl BILT mg/dl CA mg/dl CHO mg/dl CK U/L CL mmol/l CO2 mmol/l CRE mg/dl GGT U/L GLU mg/dl HDL mg/dl K mmol/l LIP u/l MG mg/dl NA mmol/l PHOS mg/dl TP g/dl TRIG mg/dl UA mg/dl UREAL mg/dl labmedicine.com July 2010 Volume 41 Number 7 LABMEDICINE 399

3 Table 2_Linearity Standard Error Test Slope (SD) Intercept (SD) of the Estimate Measured Range Expected Range ALB (0.009) 0.06 (0.03) ALP (0.004) 3.1 (2.1) ALT (0.004) 2.3 (1.6) AMY (0.011) 18.2 (12.3) AST (0.006) 0.0 (2.2) DBIL (0.025) 0.17 (0.25) BILT (0.003) 0.01 (0.04) CA (0.009) 0.10 (0.09) CHO (0.008) 3.7 (3.4) CK (0.003) 2.6 (3.7) CL (0.066) 2.06 (0.77) CO (0.007) 0.8 (0.2) CRE (0.002) 0.07 (0.04) GGT (0.005) 5.3 (3.4) GLU (0.007) 1.4 (2.7) HDL (0.009) 0.9 (0.6) K (0.010) 0.18 (0.15) LIP (0.012) 2.74 (1.61) MG (0.013) 0.07 (0.04) NA (0.014) 1.1 (2.0) PHOS (0.005) 0.04 (0.05) TP (0.010) 0.13 (0.06) TRIG (0.006) 4.5 (2.4) UA (0.016) 0.31 (0.20) UREAL (0.008) 0.7 (0.5) Table 3_Method Comparison Sample # Slope Intercept Corr Analyte (N) (Deming) (Deming) (R) ALB ALP ALT AMY AST DBIL BILT CA CHO CK CL CO CRE GGT GLU HDL K LIP MG NA PHOS TP TRIG UA UREAL Table 4_Cobas c 111 Time Study Standby to Additional First Patient Profiles Profile/Test Capacity Used Profile (min) (min) Comprehensive metabolic panel 14 tests/ (basic panel, liver function) 11 cuvettes Basic metabolic panel (GLU, CA, 8 tests/5 cuvettes electrolytes, kidney function) Liver function (ALB, TP, 6 tests/6 cuvettes ALP, ALT, AST, BILT) Electrolytes (NA, K, CL, CO2) 4 tests/1 cuvette Kidney function 2 tests/2 cuvettes (UREAL, CRE) Glucose 1 test/1 cuvette 12 1 the CL slope of is compensated by the intercept of 6.1 as results approach 100 mmol/l. The DBIL slope of supports the need for method improvement, which is also indicated by the Sigma metric of 2.36 (Table 5). Interference from bilirubin, lipids, or hemolysis was not evaluated as part of this study. LabCorp has already performed these experiments on our larger Roche/Hitachi MODULAR ANA- LYTICS systems and Roche COBAS Integra systems. The cobas c 111 has the same optics as Integra, and the reagents, calibrators, and controls are largely the same across all Roche chemistry platforms, which is an important characteristic for vertically integrated organizations seeking standardization of testing throughout testing locations. 400 LABMEDICINE Volume 41 Number 7 July 2010 labmedicine.com

4 In anticipation of multiple cobas c 111 placements throughout the LabCorp network, an inter-instrument comparison between 2 systems was performed. A serum pool was aliquoted into 5 cups for each system and 5 values obtained for each analyte from which a mean and standard deviation (SD) were derived. Acceptable interinstrument recovery was a mean bias of 5% and an individual instrument SD less than the 2 SD values of the combined data. Inter-instrument recovery passed for all analytes (data not shown). Both cobas c 111 systems were additionally challenged for potential carryover using the analytes glucose (GLU) and potassium (K). Two serum samples for GLU with high (H1, H2) and low (L1, L2) values of 358 mg/dl and 11 mg/dl respectively, and 2 serum samples for K with high and low values of 13 mmol/l and 2 mmol/l respectively, were run alternately in duplicate 10 times using the following sequence: (H1, H2, L1, L2) 10. Percent carryover determined using the formula % Carryover = [(L1-L2)/(H2-L2)] 100 gave values for both GLU and K of <0.1% on both systems (data not shown). Additionally the performance of the cobas c 111 was evaluated using sigma metrics. The calculations were performed using James O. Westgard methodology. 2 This approach uses an assay s total allowable error (TEa), accuracy (bias), and precision (SD) to calculate a Sigma metric to characterize the performance of that assay. Sigma = (TEa bias)/sd Table 5_Cobas c 111 Sigma Metrics Sigma values of 6 or greater are classified as world class and suggest the opportunity to use single rule QC with wide control limits. Decreasing sigma values of 5, 4, and <3 are classified as excellent, good, and poor respectively and reflect decreasing assay performance. A total of 23 analytes have available criteria for allowable total error (%TEa) as outlined in CLIA-88 criteria for acceptable performance. For 2 methods (CO2 and GGT) the %TEa was not available at the time of the study. Table 5 shows the cobas c 111 is very close to complete world-class performance. Only 1 method (DBIL) demonstrates some challenges (sigma 2.36 graded as a poor performance). This Sigma grade identifies DBIL as an assay in need of improvement. If imprecision could be reduced for DBIL, it is very possible that it could reach world-class performance. Seventeen out of 23 tested methods performed at the world-class level, 2 demonstrated excellent performance, and 3 demonstrated good performance. Overall, the average sigma for 21 methods (excluding ones that provided infinity sigma results due to 0 imprecision) is 16.09, which grades it as world class. While the cobas c 111 has the test menu one would expect from a larger system, one must not expect an equally Test Units Mean %CV %TEa %Bias Sigma Grade ALB g/dl World Class ALP U/L World Class ALT U/L World Class AMYL U/L World Class AST U/L World Class BILT mg/dl Infinity World Class CA mg/dl World Class CHO mg/dl World Class CK U/L World Class CL mmol/l Excellent CRE mg/dl Infinity World Class DBIL mg/dl Poor GLU mg/dl Good HDL mg/dl World Class K mmol/l World Class LIP U/L World Class MG mg/dl World Class NA mmol/l Good PHOS mg/dl World Class TP g/dl Good TRIG mg/dl World Class UA mg/dl World Class UREAL mg/dl Excellent Average: World Class large throughput. Table 4 shows the results of a time study on the cobas c 111 using the following profile or test options: comprehensive metabolic panel (GLU, CA, ALB, TP, NA, K, CO2, CL, UREAL, CRE, ALP, ALT, AST, BILT), basic metabolic panel (GLU, CA, NA, K, CO2, CL, URE, CRE), liver function tests (ALB, TP, ALP, ALT, AST, BILT), electrolytes (NA, K, CO2, CL), kidney function tests (UREAL, CRE), and GLU alone. From standby mode to results for the first, 14-test, comprehensive metabolic panel was 20 minutes, with subsequent profiles available in 10 to 11 minutes each. Examination of Table 4 shows a test throughput of approximately 1 test per minute. The patient testing rate is therefore a function of the number of tests ordered. As with all instrumentation, one must carefully manage the scheduling of patient testing on the analyzer to maximize efficiency. The cobas c 111 walk away time is controlled by the instrument s incubation cuvette capacity of 60. This translates to 60 non-ise tests that can be completed before the instrument must be placed in standby to replace disposable cuvettes. As an example, if 5 Comprehensive Metabolic Panels are scheduled on the instrument only 5 cuvettes will be available for the introduction of stat testing, via the stat interrupt process. However, if only 3 panels are scheduled at 1 time, the stat interrupt mode has 27 cuvettes available to maintain stat capability while running a large panel. While the time requirement for the pre-analytical portion is not always predictable, the analytical phase for any of the scenarios tested makes a vein to brain turnaround time of 1 hour or less achievable. Discussion The cobas c 111 is a random access analyzer with stat capability offering a mix of enzymes, substrates, serum proteins, labmedicine.com July 2010 Volume 41 Number 7 LABMEDICINE 401

5 and electrolytes suitable for a small hospital or physician office laboratory. With dimensions of 29 inches wide, 22 inches deep, and 19 inches high this bench-top system is compact, robust, intuitive, and requires minimal, system-prompted maintenance. Daily start-up and system checks are prompted by the user interface and involve: 1) a simple fluid s check (water and cleaner bottles full, waste empty), 2) less than 10 minutes of daily maintenance involving an automated probe cleaning and priming of the fluid system, 3) replacing the incubation cuvette sections as indicated by the system screen, 4) loading the reagent disk and performing system-prompted calibration and QC as needed. Weekly maintenance takes about 15 minutes, and there are system-generated prompts for all maintenance interval requirements. In addition to 3 ISE assays, 14 reagents can be loaded on each reagent disk, which is stored refrigerated in a reagent disk container when not in use. Barcoded or non-barcoded patient samples can be continuously loaded into 8 positions, and a variety of primary tubes and sample cups can be used. If the cobas c 111 is linked to a host system, results that are not flagged can be automatically accepted, and data can be downloaded to a USB stick or the laboratory information system. Standby to operation takes approximately 3 minutes. Although not evaluated in this study, the menu has since been extended to include pancreatic α-amylase, c-reactive protein, high sensitive c-reactive protein, CKMB, CRE2 enzymatic, LDL-cholesterol, lactate, lactate dehydrogenase, iron, ethanol, urine ALB2, whole blood HbA1c, and ammonia. D-dimer and homocysteine are planned for later release. The results of this study support the use of the cobas c 111 in the small laboratory niche environment of less than 60 patients per day. Management of this limitation is critical as the large test menu provides the temptation to exceed the instrument s throughput capacity. The objective is to provide timely availability of a large laboratory s menu to a limited number of patients whose medical care requires near point of service testing. Although the cobas c 111 can complete the testing of panels like the 14 assay Comprehensive Metabolic Panel, the throughput of the instrument indicates workflow for such testing should be carefully managed to allow instrument time to serve more patients who need stat testing of much fewer analytes. LM Acknowledgements: This work was carried out in close cooperation with Dr. Andrea Rose from Roche Diagnostics. We thank Daniel Whisenhunt for performing the technical and laboratory part of this study. 1. Chapman M, Padden E, Pogue S, et al. Multicenter performance evaluation of the cobas c 111 analyzer at three physician office laboratories. Clin Chem. 2007;53:A Westgard JO, Ehrmeyer SS, Darcy TP. Doing the right QC. In: CLIA Final Rules for Quality Systems. Madison WI: Westgard QC; 2004: LABMEDICINE Volume 41 Number 7 July 2010 labmedicine.com