Basic knowledge of POCT instuments The Tide Resort Bangsan Beach 18 June 2009 1
POCT instruments concepts Point of care testing Diagnostic medical devices used at or near the site of patient care Bed site, OR, ED, ICU, field, home. Provide near real time analysis and rapid test results Reduce therapeutic turnaround time Shorten length of hospital stay User friendly, Reducing dependence on operator technique. Potentially improve patient outcomes Example :Electrolyte, Hct, Blood gas and metabolites, Cardiac injury markers, Hemostatis indicator, Drugs of abuse, Infectious disease markers, Molecular diagnostics 2
Classification 3
Classification Characteristic Transportable Portable Handheld Immuno detection device Size Power source Test menu Sampling method Large and heavy On carts for mobile use AC, Batteries back up for short term use Broad test menu, Customize the tests Automatic for reducing dependence on operator technical /manual Minimize the volume of blood need per analysis. WB, P, S, U, CSF. Medium easier access to AC patients or Batteries Fixed, Single to multi test Automatic/m anual W, P, S, U Small or miniature Batteries Fixed / limited Manual WB Medium to miniature Variable to none Fixed, Single to multi test Manual WB,P, U, Saliva 4
Classification Characteris tic Instrument Electrode/se nsor, Reagent Calibration Transportable Portable Handheld Immuno detection device Blood gas system. The electrode/sensor, reagents, cartrige/cuvette are separated and removable. Automatic internal one and two point calibration that is performed periodically Blood gas, PT,aPTT, HbA1c, Chemistry, The electrode /sensors and reagents are built and packaged within the disposable cartridge. Periodic or prior to testing depend on multiple or single use cartridges Blood gas, Glucose meter The electrode and biosensor are constructed in to the test strips, Dryreagent Don t chemistry have internal calibration but have electronic verification steps Cardiac testing, Drug abuse, D-Dimer No calibration is needed 5
Classification Characteristic Transportable Portable Handheld Immuno detection device Biohazard LIS connectivity Password security Build in biohazard container Available Available Build in biohazard container Possibly available Possibly available Lack of waste storage, Exposed to biohazards Limited Limited Biohazard storage none none 6
Principle Amperometer CoaguChek XS 7
Reflectance photometry 8
Reflectance of u 411 9
Reflectance of h232 with CCD (Charge couple devices) Digital camera chip 10
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QC Conventional method Manual external introduction Automatic QC testing Omni system Automatic draw QC materials which are onboard at operator defined schedule Intelligent quality control ( iqc ) Piccolo system (Abaxis) USA Verifies the chemistry, Optics and Electronics function of the analyzer during each run. No operator interaction 12
QC The integrated Quality Control (QC) function The fill detect system will indicate that an adequate sample has been applied to the test strip. Checks each test strip. Misuse, such as improper storage of the test strip in hot and humid environment as well as exposure to extended ambient light, can be detected by the system. In the case of misused test strips a QC error will be displayed on the device. 13
QC Electronic quality control Available portable and handheld instruments Supplements the traditional liquid QC procedures Evaluation of the optics, electronic and computational component of the system Does not validate the performance and functionality of the cartridge. Is not designed to replace liquid QC testing 14
Potential sources of errors in POCT Pre-analytic Patient identity Specimen collection Incorrect, mishandled, expired, unlabeled or unstable of test strips, cartridges, cassettes, or reagents Leukocytosis > 50,000 /ul, Thrombocytosis >600,000/ul, anemia (Hb < 7.5 g/dl), ph, Osmolarity, protein, lipid, heterophile Ab, Autoimmune Direct or indirect effects of transfused blood products or additives Analytic Physical (Temp, altitude, vibration, humidity) Sample (bubbles,viscosity, thrombi Calibration protocol not followed, calibration code wrong Sensor drift, aging Newborn glucose limits Lack of IQC, EQA, PT Operator not qualified, certified Maintenance Unstable power source 15
Potential sources of errors in POCT Post-analytic Critical values omitted, not recognized Wrong units, No results documentation No LIS No patient demographics 16
Selection and Evaluation of POCT System performance Broad test menu Accuracy, precision, resolution, reproducibility, stability, and response time Linearity Relationship to tests performed in the main lab Compatibility with other in vitro, ex vivo, in vivo Artifact elimination, error detection, interference warning and specimen flagging Technical and quality features Throughput, automated calibration, interrupt capability, duration of analysis cycle Compact, reliable, durable, light weight, mobile, and power efficient with battery operation Reagent stability, shelf life, lot size Continuous quality improvement (quality control, quality monitors, proficiency testing) Compliance with federal, state and accreditation regulation 17
Selection and Evaluation of POCT Conservation of patient blood volume Specimen volume type and matrix (eg.,whole blood, plasma, or serum) accepted Safety, ergonomics, security, and risk Biohazard control, containment, and disposal Speed, ease, simplicity and user friendly operation Economic efficacy Flexibility, Modularity, Exchangeability, expandability and upgrade capability Cost of instruments, consumables, and maintenance 18
Selection and Evaluation of POCT Information interpretation and integration Remote review, remote control, and data management system Networking interfacing and wireless communications and critical results notification 19
Top 5 requirements for POCT Accurate and precise results that correlate with the laboratory Easy to use Customer support Low cost solutions Connectivity including data management 20
Method validation Moderately complex test methodology Comparison of method (accuracy) Replication experiment (precision) Linearity experiment (reportable range) Verification of reference range Highly complex test methodology A waived or moderately complex test methodology, if modified by the user, automatically become high complexity Comparison of method (accuracy) Replication experiment (precision) Linearity experiment (reportable range) Detection limit experiment (Sensitivity) Interference experiment Recovery experiment Extensive reference range 21
Imprecision Glucose No. L1 L2 1 99 282 2 99 277 3 99 281 4 98 280 5 99 278 6 99 278 7 98 278 8 99 283 9 99 278 10 96 279 11 97 276 12 95 281 13 96 275 14 99 276 15 98 278 16 98 280 17 98 284 18 97 281 19 98 281 20 98 283 MEAN 98.0 279.40 SD 1.19 2.01 %CV 1.22 0.72 Criteria of acceptant Imprecision N 20 Level 2 Within run or between run 0.25*TE Between run 0.33*TE Example TE Glucose = 10% Criteria of within run 2.5% L1 = 1.22 PASS L2 = 0.72 PASS 22
Comparison chart No RXL GLUCOSE (mg/dl) c501 1 82 90 2 76 86 3 87 98 4 79 84 5 87 96 6 264 283 7 50 53 8 200 219 9 86 92 10 102 107 11 84 91 12 113 118 13 93 100 14 105 113 15 118 126 Correlation ( r ) 0.9991 Slope 1.0741 Y-Intercept 0.6396 T-TEST 0.6761 c501 300 250 200 150 100 50 C501 & RXL y = 1.0741x + 0.6396 R 2 = 0.9983 50 100 150 200 250 300 Minimum criteria N = 20, 40 RXL Duration = with 2 hrs / 5 days r < 0.99 r 2 < 0.95 23
Criteria of acceptant Inaccuracy SE + RE = % Bias + (3*% CV ) Bias = ( (x c * b) + a ) x c = (100 * 1.0741) + 0.6396 = 108.04-100 = 8.04 %Bias = Bias * 100 / x c = 8.04 *100/100 = 8.04 %CV = 3*1.22 = 3.66 %Bias + (3* % CV) = 8.04 + 3.66 = 11.7 FAIL TE Parameter Within Run Precision Acceptable %CV Comparison a b Xc SE %bias %RE TEcal %TEa conc. %CV 1/4 of TEa between intercept slope Yc-Xc value Absol ute (CV) % 98 1.22 2.5 0.6396 1.0741 120 9.5257 7.9 7.9 1.22 11.6 10 C1 &RXL Glucose 279 0.72 2.5 0.6396 1.0741 180 13.969 7.8 7.8 0.72 9.9 10 99 1.82 2.5 3.2898 0.9846 120 1.4406 1.2 1.2 1.82 6.7 10 C1 & C2 241 0.68 2.5 3.2898 0.9846 180 0.516 0.3 0.3 0.68 2.3 10 24
Precision chart 25
Comparison chart 26
The linearity or Reportable range Experiment Clinical and Laboratory Standards Institute (CLSI) recommends a minimum of at least 4 and preferably 5 different levels or concentration Materials standard solutions linearity set from manufacturers proficiency testing agencies pools of patient specimen when high values are available in some cases e.g.tdm spike a pool with the analyte to be measured Selection of the diluent General chemistry tests; water and saline will be OK For other tests; better to use bovine or serum albumin preparations; specimen with low concentrations; drug free serum Follow the manufacturer s recommendation of the diluent to use 27
Linearity Procedure for preparation specimen 2 pools; one near the zero level or close to detection limit. The other near or slightly above the expected upper limit of the working range Pool1 : low pool Mixture2 : 3 parts pool1+1 part pool5 Mixture3 : 2 parts pool1+2 part pool5 Mixture4 : 1 part pool1+3 part pools5 Pool5 : high pool Mix 1 Mix 2 Mix 3 Mix 4 28
Linearity Number of replicate measurements NCCLS recommends 4 measurements on each specimens 3 replicates are generally sufficient. Pool or Mixture Mean (Y) Theoretical (X) % Recovery Pool 1 Mean value Mean pool 1 Y1*100/X1 Mixture 2 Mean value (Mean pool1 * 3) + (Mean pool5 * 1)/4 Y2*100/X2 Pool1 : Pool5 3 : 1 Mixture 3 Mean value (Mean pool1 * 2) + (Mean pool5 * 2)/4 Y3*100/X3 Pool1 : Pool5 2 : 2 Mixture 4 Mean value (Mean pool1 * 1) + (Mean pool5 * 3)/4 Y4*100/X4 Pool1 : Pool5 1 : 3 Pool 5 Mean value Mean pool 5 Y5*100/X5 29
Linearity Theoretical value Measment value % Recovery Pool 1 0 0 #DIV/0! Mixture 2 200 205 102.5 Mixture 3 400 418 104.5 Mixture 4 600 585 97.5 Pool 5 800 820 102.5 Linearity experiment 1000 800 600 400 200 0 0 200 400 600 800 1000 %Recovery 110.0 105.0 100.0 95.0 90.0 Linearity experiment Mix 2 Mix 3 Mix 4 Pool 5 1 2 3 4 Dilution 30
Verify reference interval Criteria Transference technique Reference population N= 20 Blood donor Hospitalization Alcohol consumption Blood pressure abnormal Drug abuse Tobacco use Pregnancy Oral contraceptives etc,. 95% percentile acceptable N = 20 criteria acceptance 1 that out of reference range 31
Sensitivity or Detection limit experiment Analytical sensitivity (lower detection limit) Immunology The detection limit represents the lowest analyte level that can be distinguished from zero. It is calculated as the value lying two standard deviations above that of the lowest standard (master calibrator, (standard 1 + 2 SD, within-run precision, n = 21). Chemistry The lower detection limit represents the lowest measurable analyte level that can be distinguished from zero. It is calculated as the value lying three standard deviations above that of the lowest standard (standard 1 + 3 SD, within-run precision, n = 21). 32
Sensitivity or Detection limit experiment The limit of blank (LoB).. The limit of blank corresponds to the concentration below which analyte free samples are found with a probability of 95%. LoB = mean blank + 1.65 SD blank The limit of detection (LoD). The limit of detection corresponds to the sample concentration which leads with a probability of 95% to a measurement result above the limit of blank. LoD = LoB + 1.65 SD blank The limit of quantitation (LoQ) is the lowest concentration that can be reproducibly measured with the between run coefficient of variation of < 20%. LoQ = Bias spike + 2SD spike 33
Criteria of acceptance 34
Waived tests requirements by accrediting agency Requirement CLIA JCAHO CAP Daily QC requirement Participation in regulatory proficiency testing Establishment of accuracy (twice each year) for analytes not in proficiency testing Method verification before implementation Method verification before implementation for multiple instrument, same model Follow test manufacturer s direction Only for CLSI regulated analytes Follow test manufacturer s direction Only for CLSI regulated analytes Yes Yes Yes No Accuracy, precision, reportable range, and appropriateness of reference ranges No No Yes Doesn t recognize waived testing. All tests must meet the same standards For all analytes when proficiency test is available Accuracy, precision, reportable range, sensitivity and appropriateness of reference ranges 35
Selected POCT requirements Requirement CLIA JCAHO CAP Assessment of accuracy at least every 6 months Assessment of reportable range every 6 months No Yes Yes No No Yes Method correlation at least every 6 months For test results from different methodologies under the same CLIA certificate For test results from different methodologies across entire JCAHO For test resutls from different methodologies under the same CLIA certificate Moderately complex testing QC for most analytes 2 levels of QC per day. More frequent evaluation is required for some analytes 2 levels of QC per day. More frequent evaluation is required for some analytes 2 levels of QC per day. More frequent evaluation is required for some analytes 36
Selected POCT requirements Requirement CLIA JCAHO CAP Accepts electronic controls Yes, follow manufacturer s recommendation Yes, with verification of manufacturer s claims and periodic assessment with liquid controls Yes, with verification of manufacturer s claims and periodic assessment with liquid controls CAP,College of American Pathologists, CLIA, Clinical Laboratory Improvement Amendments, JCAHO, Joint Commission on Accreditation of Healthcare Organizations. 37
Selected POCT requirements Requirement CLIA JCAHO CAP Non waived test Unmodified Moderate and high complexity Accuracy Precision Reportable range Verify reference range Accuracy Precision Reportable range Verify reference range Accuracy Precision Reportable range Non waived test Modified or developed in house Accuracy Precision Reportable range Verify reference range Analytical sensitivity Analytical specificity (interfering substances) Recovery Accuracy Precision Reportable range Verify reference range Analytical sensitivity Analytical specificity (interfering substances) Accuracy Precision Reportable range Analytical sensitivity Analytical specificity (interfering substances 38
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