S1828 New External Programs for Laboratory Quality Assurance

Transcription

1 S1828 New External Programs for Laboratory Quality Assurance Keri J. Donaldson, MD, FCAP Charles S. Eby, MD, FCAP Anthony A. Killeen, MD, PhD, FCAP

2 Objectives Identify the new CAP and CMS requirements for quality assessment Describe the importance of commutable PT samples Explain the importance of multiple instrument comparisons Apply AMR validation and linearity to coagulation testing 2

3 Quality Cross Checks How to Monitor Performance of Multiple Instruments and Stay in Compliance Keri J. Donaldson, MD, FCAP

4 Learning objectives Describe CMS regulations regarding performing proficiency testing (PT) on multiple instruments Describe new requirements for CAP-accredited laboratories performing waived whole blood glucose testing using glucose meters versus other methods Describe how laboratories can monitor performance of glucose meters across their laboratories 4

5 CMS regulations regarding PT on multiple instruments In 2013, CMS reiterated how PT should be handled for regulated analytes Treat PT like patient samples Laboratories are only permitted to test PT specimens and report results for one instrument/method during the PT event unless that is how you test patient samples PT event is defined as the time from when specimens arrive in the laboratory through due date on result form Result multiple instrument reporting eliminated for regulated analytes for 2014 Surveys cycle 5

6 CMS regulations regarding PT on multiple instruments In 2015, CMS further clarified that this applies to all analytes including those not listed in Subpart I of the CLIA regulations: Non-regulated analytes including waived analytes Result multiple instrument reporting eliminated for nonregulated (including waived) analytes for

7 What does this mean for the laboratory? Each individual CLIA-licensed laboratory is allowed: 1 PT Result per Analyte Specimen per Type 7

8 PT programs with different specimens can be used to test the same analyte Sodium performed on an analyzer in the main laboratory and on i-stat in the POC setting Different PT Surveys exist for serum/plasma and whole blood sodium thus both programs can be performed and reported 8

9 What does this mean for laboratories with multiple glucose meters? In 2016, laboratories enrolled in Whole Blood Glucose Surveys (WBG, WB2) could only test and result one glucose meter during the PT event. After the due date on the original result form laboratories could report their additional meters on a second result form. For CAP-accredited laboratories this meant that only the results of the single meter reported during the PT event was monitored. Regulatory risk for laboratories. 9

10 CAP Laboratory Accreditation Program (LAP) requirement changes in 2017 Beginning in 2017, the following PT will no longer be required or monitored: Waived whole blood glucose on glucose meters (WB2/WBG discontinued) Waived whole blood Protime/INR (WP9, WP10 available; not required) PT requirement for LAP-based upon medical importance, availability of Surveys material, and ability to grade and monitor performance 10

11 CAP Laboratory Accreditation Program (LAP) requirement changes in 2017 Laboratories will be required to perform alternative performance assessment for these analytes Activity menus updated to separate waived WB glucose performed on meters (no PT enrollment required) from waived WB glucose methods performed on instruments like i-stats or Hemocues (PT enrollment required) 11

12 Alternative performance assessment COM For tests in which the CAP does not require PT, laboratories are required to complete alternative performance assessment semi-annually This LAP checklist requirement applies to both waived and nonwaived tests 12

13 Alternative performance assessment procedures External PT program Ungraded/educational PT program Split sample analysis with reference or other laboratories Split sample with an established in-house method Assayed materials Clinical validation by chart review Other suitable and documented means 13

14 Laboratory director responsibilities Define alternative assessment procedures Define criteria for successful performance Document the review of results of all alternative assessments Make these records available to inspectors Investigate and perform corrective action for all unacceptable results 14

15 Evidence of Compliance List of tests that require alternative performance assessment Must be maintained by laboratory, all tests performed that do not require enrollment in PT Records of the all the alternative assessments Including the evaluation criteria and documentation of each unacceptable result 15

16 Alternative performance assessment Waived Whole Blood Glucose using Glucose Meters The CAP is discontinuing Whole Blood Glucose Surveys in 2017 WBG and WB2 Quality Cross Check Whole Blood Glucose fulfills LAP s requirement for alternative assessment 16

17 What is Quality Cross Check? 17

18 CAP Quality Cross Check programs Quality assurance programs that allow comparison and monitoring of multiple instruments on a routine basis, whether within or across laboratory sites 18

19 Quality Cross Check programs are not PT Quality Cross Check complements your existing CAP Surveys Results are not submitted to any regulatory agency Programs are not subject to CMS restrictions regarding PT Allows for testing of all specimens when you receive them on multiple instruments 19

20 Benefits of using Quality Cross Check Convenient solution for alternative performance assessment Eliminates the need to prepare split samples or send samples to a reference laboratory Opportunity to participate in an external assessment and be evaluated against peers Easy-to-use program that offers a turn-key solution for biannual comparability testing 20

21 Benefits of using Quality Cross Check Opportunity to fulfill staff competency requirements Identifies instrument problems before they impact patient results Provides an early alert before PT failures occur 21

22 Quality Cross Check meets requirement for biannual comparability testing of nonwaived testing Biannual comparison studies must be performed if more than one instrument/method is routinely used for patient testing (COM.04250) Instrument used during PT event can be included using Quality Cross Check to make the most of the comparability statistics 22

23 How does Quality Cross Check work? Participants receive three challenges in each of two mailings a year with specimens that span the clinical range Shipments are spaced between PT shipments to allow for more frequent monitoring Quality Cross Check Whole Blood Glucose is shipped twice per year to meet your alternative assessment requirements Participants can report up to three instruments for each challenge The new Whole Blood Glucose program allows laboratories to report up to 30 meters 23

24 Quality Cross Check evaluations Peer group comparisons Peer group assignment Targets Acceptability limits Graphical summary of deviation Instrument comparisons Participant Summary Report 24

25 Quality Cross Check Programs Whole Blood Glucose (WBGQ) Parathyroid Hormone (PTHQ) Automated Hematology (FH3Q, FH4Q, FH6Q, FH9Q) Urinalysis (CMQ) Occult Blood (OCBQ) Coagulation (CGLQ) Activated Clotting Series (CTQ, CT1Q, CT2Q, CT3Q, CT5Q) Critical Care Aqueous Blood Gas (AQQ, AQ2Q, AQ3Q, AQ4Q) Blood Oximetry (SOQ) General Chemistry and Therapeutic Drug Monitoring (CZQ) B-type Natriuritec Peptides (BNPQ) Body Fluid (FLDQ) Hemoglobin A 1c (GHQ) 25

26 Quality Cross Check Whole Blood Glucose Monitor 30 glucose meters with 3 challenges shipped twice per year Ability to test and submit results for up to 30 meters all at one time Program utilizes established PT grading criteria Fulfills the requirement for alternative performance assessment for waived glucose testing using glucose meters 26

27 Quality Cross Check Whole Blood Glucose 27

28 Quality Cross Check Whole Blood Glucose 28

29 Summary Beginning in 2017, PT will no longer be required or monitored: Waived whole blood glucose on glucose meters (WB2/WBG discontinued) Waived whole blood Protime/INR (WP9, WP10 available; not required) For tests in which the CAP does not require PT, laboratories are required to complete alternative performance assessment semi-annually This LAP checklist requirement applies to both waived and non-waived tests 29

30 Calibration and Analytical Measurement Range (AMR) verification collides with coagulation testing Charles Eby, MD Co-Chief Division of Laboratory and Genomic Medicine Washington University School of Medicine In St. Louis 1

31 Speaker Financial Disclosure Information CAP Instrumentation Resource Committee member CAP Continuous Compliance Committee member Instrumentation Laboratory Siemens Healthcare Diagnostics 2

32 Coagulation testing is the most analytically rigorous lab medicine discipline Thumbs up/down 3

33 Objectives Review concepts, definitions, and CAP requirements for calibration and AMR Identify coagulation assays requiring calibration and AMR verification Understand value of calibration and AMR periodic evaluation Special thanks to Russell Higgins, MD, UT San Antonio for granting permission to use some of his figures and tables 4

34 CLIA 88 terminology CAP 2003 terminology CLIA and CAP terminologies are not identical Relationship Between Calibration Verification and AMR Calibration Verification Calibration Verification AMR Evaluation Commutable Accuracy Accuracy and Linearity Frequency At least every 6 months or Change in active reagents QC fails to meet criteria Major maintenance/service Per manufacturer Per lab director s discretion At least every 6 months or Change in active reagents QC fails to meet criteria Major maintenance/service Per manufacturer Per lab director s discretion Materials Calibrators Patient Samples, unaltered Standards/Reference materials (commutable) Proficiency testing material Vendor material for calibration verification Calibrators Patient samples, unaltered or altered Standards/Reference materials Proficiency testing material Controls with method specific values 5

35 2018 LAP checklist items HEM Calibration Procedures Phase II Calibration procedures for each method are adequate, and the calibration results are documented. HEM Calibration/Verification Criteria Phase II Criteria are established for frequency of recalibration or calibration verification, and the acceptability of results. HEM Recalibration Phase II The method system is recalibrated when calibration verification fails to meet the established criteria of the laboratory. HEM AMR Validation Phase II Validation of the analytical measurement range (AMR) is performed with matrix-appropriate materials, which include the low, mid and high range of the AMR, appropriate acceptance criteria are defined, and the process is documented. HEM Diluted or Concentrated Samples Phase II If a result is less than or greater than the AMR, a numeric result is not reported unless the sample is processed by dilution, a mixing procedure or concentration so that the processed result falls within the AMR. HEM Maximum Dilution Phase II For analytes that may have results falling outside the limits of the AMR, the laboratory procedure specifies the maximum dilution that may be performed to obtain a reportable numeric result.

36 Instrument signal converted to quantitative result = Calibration [Instrument Signal] Calibration Curve [Reference Concentration] CALIBRATION function: relationship between instrument signal and the corresponding concentration/activity of an analyte. 7

37 CALIBRATION VERIFICATION: the process of confirming the current calibration settings are valid [Instrument Signal] Calibration Curve [Reference Concentration] [Measured Concentration ] Linear Recovery [Reference Concentration] 8

38 Recalibration can satisfy calibration verification 9

39 AMR-CAP definition The ANALYTICAL MEASUREMENT RANGE is the range of analyte values that a method can directly measure on the specimen without any dilution, concentration, or other pretreatment not part of the usual assay process. This means there should be a linear relationship between expected and measured analyte values when specimens of known value are mixed with other specimens of known value at different ratios: i.e. linear dilutional recovery. This range may be established by the manufacture or in the laboratory 10

40 Which combination of sample number and range satisfies CAP AMR verification? A. 3, low, medium, high B 2, low, high C. 4, distributed in quartiles D. At the medical director s discretion 11

41 Which combination of sample number and range satisfies CAP AMR verification? A. 3, low, medium, high B 2, low, high C. 4, distributed in quartiles D. At the medical director s discretion 12

42 Validating AMR with Patient Samples 1:1 High Concentration [Observed Concentration] Low Sample Relative Concentration Expected High 100% 200 U/ml 1:1 50% 105 U/ml Low 0% 10 U/ml [Expected Concentration or Relative Concentration] 13

43 confusing AMR-like terminology Dynamic range Working range Reportable range for undiluted samples Linearity Measuring range

44 If > 3 calibrators cover the AMR 250 Line Fit Poly. Fit 200 Measured (%) Calibrated Range Assigned (%) 200 AMR 250 separate AMR verification exercise is not required 15

45 If calibrators do not cover the AMR 250 Line Fit Poly. Fit 200 Measured (%) Calibrated Range Assigned (%) 200 AMR 250 Or <3 calibrators then a separate AMR verification procedure is required 16

46 Back to AMR defn: range of analyte values without dilution, concentration, or other pretreatment not part of the usual assay process Concentrated Range not requiring calibration verification AMR requires verification at least every 6 months Maximum concentration/ dilution requires review every 2 years 17

47 What year did CAP add Cal/AMR verification to Coagulation LAP Checklist? A B C D. No one knows for sure 18

48 What year did CAP add Cal/AMR verification to Coagulation LAP Checklist? A B C D. No one knows for sure 19

49 2012: LAP checklist introduces calibration and AMR verification to coagulation testing Chemists and Cal/AMR Long history- Vendors have adapted Package insert information Linearity/calibration products Reference standards available Recalibrate infrequently Coag lab directors and Cal/AMR We re clotters not chemists! Vendors following, not leading Few, if any, commutable standards Instrument issues Autodilution Manufacturer calibration

50 Are All Hemostasis methods so different from routine Chemistry methods? 21

51 CAP Coagulation Resource and LAP Checklist committees Decision Cal/AMR verification applies to hemostasis tests based on direct measurement of concentration or activity of an analyte by a quantitative, calibrated method: Chromogenic, Enzyme Immunoassay, Fluorescence Immunoassay, and Immunoturbidity methods Cal/AMR verification does not apply to: clot based tests and platelet function testing 22

52 Which coagulation test is exempt from LAP Cal/AMR verification? A. von Willebrand factor antigen B. D-dimer C. Heparin/low molecular weight heparin D. INR 23

53 Which coagulation test is exempt from LAP Cal/AMR verification? A. von Willebrand factor antigen B. D-dimer C. Heparin/low molecular weight heparin D. INR 24

54 Hemostasis tests Not requiring Cal/AMR Verification Non-calibrated tests Prothrombin time (PT) and INR Activate partial thromboplastin time (APTT) Thrombin Time (TT) Lupus anticoagulant testing Platelet aggregation/ristocetin cofactor activity Activated Clotting Time PFA-100 Thromboelastometry VerifyNow Calibrated tests Clot-based factor activities (factors XII, XI, X, IX, VIII, VII, V, II) Clot-based protein S and protein C activities Clot-based fibrinogen activity 25

55 Hemostasis tests Requiring Cal/AMR Verification Calibrated Immunoassays D-dimer Von Willebrand factor (VWF) antigen VWF activity: glycoprotein Ib binding assay Free protein S antigen Calibrated Chromogenic assays Antithrombin activity Protein C activity anti-xa methods: heparin, LMWH 26

56 Hemostasis Cal/AMR verification Challenges Medical Director decisions Acceptable material, AMR coverage, acceptable error Extended AMR calibrated clotting tests-fibrinogen Compliance and documentation Instruments with different calibration schemes Calibrated by manufacturer Calibration verification with only two levels locally No calibration verification material whole blood point-of-care D-dimer 27

57 CAP products for Hemostasis Cal/AMRlinearity verification: CVL Chromogenic Anti-Xa heparin/lmwh Protein C activity Antithrombin activity Immuno-turbidity D-dimer Von Willebrand antigen Clot-based Fibrinogen 28

58 Performance of CVL Participants Antithrombin: Protein C: VWF:Ag: 29

59 Performance of CVL Participants D-dimer: 30

60 Uncovering instrument reagent inaccuracy thru CVL survey-personal experience IL D-dimer HS assay Immuno-turbidity, quantitative ng/ml D-DU Pkg insert: linear range ng/ml QC stable: low: 390 ng/ml; High 870 ng/ml Subscribe to CAP CVL D-dimer survey for LAP Cal/AMR verification requirements 31

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63 Re-calibrated and repeated CVL samples VTE cutoff:

64 Fibrinogen CVL-enhances quality Clinical decision range 35

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66 CVL meets most of my laboratory s coagulation Calibration/AMR verification requirements Analyte Vendor linearity Lab AMR CVL range Extra lab AMR verification? Antithrombin % NO Protein C % NO vwf Ag % YES Heparin IU/ml * NO D-dimer ng/ml D-DU ,000^ 70-2,400 NO *AMR , extended to 4.0 re-verified q 2 years ^AMR , extended to 40,000 re-verified q 2 years 37

67 Summary: Hemostasis testing and Calibration/AMR Verification Same principles as apply to many chemistry analytes Required for quantitative immunoassay and chromogenic methods Does not apply to clot-based assays (CAP) but principles can apply to fibrinogen activity and coagulation factor activities CAP CVL surveys are an option for LAP compliance and are performing well 38

68 New External Programs for Laboratory Quality Assurance Anthony A. Killeen, MD, PhD Professor, Dept. of Laboratory Medicine & Pathology University of Minnesota

69 Disclosures No financial disclosures related to his talk Salary from University of Minnesota and University of Minnesota Physicians Grant support from NIH No off-label use of drugs Prior volunteer as Chair or Member of College s Chemistry Resource Committee, Instrumentation Resource Committee; currently Chair of Accuracy-Based Testing Commitee 2

70 Outline Introductory overview of EQA/PT What can we learn (and not learn) about accuracy from PT testing? Current state of accuracy-graded PT tests 3

71 PT Requirements in 2018 CLIA 88 mandates PT for 87 regulated analytes List remains the same as in 1992 Important new markers (BNP, troponins, molecular tests) not included Usually 5 samples shipped 3 times/year Passing score is 80% (100% in some cases) CAP usually requires formal PT where available 4

72 Some Passing Scores ALT ±20% Albumin ±10% Alkaline ph tase ±30% Amylase ±30% AST ±20% Bilirubin ±0.4 mg/dl or ± 20% (greater) CK Isoenzymes: MB elevated or present/absent or target ±30% Cholesterol ±30% Cortisol ±20% Free T4 ±3 S.D. hcg ±3 S.D. or pos/neg Blood gas po2: Target value ±3 S.D. 5

73 Not All Labs Must Do PT Labs that hold CLIA Certificates of Compliance or Accreditation are required to perform PT and can be penalized for failure Labs that hold CLIA Certificates of Waiver are exempt from federal PT requirements have less stringent personnel requirements growing in number 6

74 Chemistry/Endocrinology Regulated Analytes Albumin Blood ph Creatine kinase isoenzyme Potassium Free Thyroxine Alkaline phosphatase Blood gas po2 Creatinine Protein, total Serum pregnancy test (HCG) ALT/SGPT Calcium, total Glucose Sodium T3 Uptake Amylase Chloride Iron, total Triglycerides Triiodothronine AST/SGOT Cholesterol, total Lactate dehydrogenase Urea nitrogen (BUN) TSH Bilirubin, total HDL Cholesterol LDH isoenzyme Uric acid Thyroxine Blood gas pco2 Creatine kinase Magnesium Cortisol 7

75 What is Accuracy? How accurate is a test? Clinical accuracy How well does a test classify health vs. disease, or different stages of disease? How accurate is a test result? Analytical accuracy Closeness of agreement between a test result and the accepted reference value (ISO 5725) 8

76 Common Terms In Metrology Precision Closeness of agreement between independent test results obtained under stipulated conditions Trueness Closeness of agreement between the average value obtained from a large series of test results and the accepted reference value 9

77 Accuracy/Trueness Matter Enables us to use common reference intervals, treatment strategies, and risk assessment tools for patients Viljoena A, Twomey PJ: J Clin Pathol 2007;60: Patients move between clinics (and labs) Practice guidelines should be applicable beyond just the original study populations 10

78 Methods Have Levels of Accuracy METHOD ACCURACY SETTING EXAMPLE (Cholesterol) Definitive ± % National/international standards labs Reference method Field methods ±1 2 % Standards labs, professional organizations, manufacturers IDMS Abell-Kendall ±3 5% Clinical labs Cholesterol esterase Source: Cali JP: Pure & Appl Chem 45:63-8, 1976 with modification 11

79 ISO 17511: 2003 Categories for Calibration Traceability Category RMP Primary (pure substance) Ref. Material Secondary (value assigned) Ref. Material Examples 1 Yes Yes Possible Electrolytes, glucose, cortisol 2 Yes No Possible Enzymes 3 Yes No No Hemostatic factors 4 No No Yes Proteins, tumor markers 5 No No No EBV, CMV 12

80 Possible Levels of Agreement Standardized Results are equivalent, higher-order RMP exists, primary reference material available for calibration Harmonized Results are equivalent, traceable to a reference material, or based on consensus, but no higher order RMP, no primary reference material exists 13

81 Are Accuracy or Harmonization Needed for Clinical Practice? Yes, for certain analytes where recommended clinically defined limits ( cut points ) are established But, clinical recommendations for defined limits often fail to consider the state-of-the-art in laboratory practice (accuracy) 14

82 Some Reasons for Differences in Assay Results Differences in calibration (trueness) Differences in assay precision Differences in molecules being measured Differences in interferences 15

83 Important Clinical Decisions are Often Based on Cutoff Points Cholesterol lowering therapy Diabetes diagnosis (glucose or HbA1c) CKD detection (creatinine, albuminuria) Manage newborns with hyperbilirubinemia Testosterone deficiency/replacement Etc. 16

84 Examples of Challenging Analytes TSH hcg PSA Troponin I Natriuretic peptides CEA Complex molecules Multiple forms Closely related molecules Relative concentrations of different forms vary in health and disease LH Vitamin D vitamers 17

85 Factors in Lab Performance Internal activities Quality Assurance Program Quality control monitors Clinical correlation of test results Evaluation of unusual/unexpected results External monitors Proficiency testing Has tended to focus on regulatory component Can provide important insights into method performance 18

86 Lessons from the Fresh Frozen Surveys Fresh frozen serum surveys (1993, 2003) Fresh pooled serum samples mailed to participants in C- Survey Reference method assigned values (some analytes) Two recurring lessons Biases widespread (differences between methods and from reference method values) Routine PT materials are not commutable 19

87 Accuracy-Graded Surveys are the Norm in other Fields! Microbiology Blood Banking Molecular Genetics Cytopathology (GYN) Cytogenetics Etc. 20

88 Assessing Harmonization and Accuracy from PT Survey Data Harmonization: results agree within clinically acceptable limits between different methods and manufacturers A goal of several organizations, e.g., CLSI, ISO, the EU, is to use commutable reference materials for method calibration traceability and PT programs A commutable PT material is one in which the numeric value of an analyte concentration or activity is equivalent to that of a native clinical specimen containing the same concentration/activity 21

89 Many PT Materials Are Not Commutable PT materials (chemistry) are manufactured Not possible to achieve all PT targets with real samples Artificial materials have matrix effects Magnitude of matrix effects is unpredictable between different methods and instruments 22

90 Why Do Matrix Effects Matter? If PT materials were commutable, results between field methods, and between field methods and a reference method could be compared directly Differences observed would be due to Calibration bias (trueness) Random bias (imprecision) 23

91 In practice, differences are attributable to Calibration bias (will affect patient samples) Random bias (will affect patient samples) Matrix effects (an artifact of PT materials) A matrix effect can mask a calibration bias Perennial question If method A and method B give different PT results, is there a calibration bias or matrix effect? 24

92 Why use artificial PT materials? CLIA Routine chemistry.(a) Program content and frequency of challenge. To be approved for proficiency testing for routine chemistry, a program must provide a minimum of five samples per testing event. There must be at least three testing events at approximately equal intervals per year. The annual program must provide samples that cover the clinically relevant range of values that would be expected in patient specimens. Source: CLIA Regulations 25

93 2010 U-C Survey 26

94 How to Grade PT Results? Peer-group grading Participants are usually graded relative to the mean of their peer group Allows participants to judge if their results differ from those of other users of the same method because of local calibration bias (ME should affect all peers equally) 27

95 Peer group mean bias vs. IDMS, mg/dl ABBOTT BAYER NOVA SCHIAPPARELLI TOSHIBA BECKMAN DADE ROCHE VITROS OLYMPUS 28

96 Creatinine today vs : biases ranged from -7% to + 34% now: biases ranged from -5 to +10% (with samples of ~0.7 to 0.9 mg/dl) All egfr calculations expected to be within 2-3 ml/min/1.73 m 2 of actual value Caveat: differences in number of labs (and quality?) (C- Survey vs. LN24 Survey) 29

97 Improvements in Creatinine, four most common methods (LN24) Killeen et al., APLM

98 Vitamin D ABVD, 2012 (Native Human Serum, Reference Value Target; Accuracy Based) Mailed 4/2/12 No. Labs Mean S.D. C.V. Median ABVD-06 Abbott Architect i Target = 29.4 ng/ml DiaSorin Liaison DiaSorin RIA Immunodiagnostic Systems LC-MS-MS Siemens Diagnostics ADVIA Centaur/XP Y-A Survey, 2012 (Conventional PT Material) Mailed 4/23/12 No. Labs Mean S.D. C.V. BGS-03 Abbott Architect i Target = 25 ng/ml DiaSorin Liaison DiaSorin RIA Immunodiagnostic Systems EIA Immunodiagnostic Systems isys LC-MS-MS Mass Spectrometry Siemens Diagnostics ADVIA Centaur/XP

99 History of A1c Improvement 1993: AACC formed a committee to standardize A1c measurement 1996 : NGSP initiated 1995: IFCC formed a workgroup to develop higher order reference method and materials 2001: IFCC reference method approved Gradual and ongoing improvement by manufacturers during the first decade C21 32

100 Improvements in HbA1c, (% Labs Reporting A1c) 50% 80% ~100% 100% Source: Sacks et al. Clin Chem 57: ,

101 Current Limiting Factors in Providing Accuracy- Based PT Materials Cost of production is higher than routine materials Limited possible ranges of analyte concentrations E.g. where to get high troponin samples? Politics of failing participants subscribe to BGN, not ABVD Lack of reference methods for many analytes 35

102 2018 ABS Offerings ABL: Lipids (apo A1, apo B, cholesterol, HDL-C, LDL-C, Lp(a), triglycerides) ABVD: Vitamin D (25-OH-D2/3) NB, NB2: Neonatal bilirubin ABS: Testosterone, estradiol, calcium, cortisol, TSH ABU: Urine albumin, creatinine (A/C ratio), calcium LN24: Creatinine (spiked high pool) ABTH: [Harmonized] T3, T4 (both total and free), TSH GH2 and LN15: HgbA1c 36

103 General Conclusions Extensive variability between manufacturers and methods for many chemistry analytes Harmonization will require a lot of effort Many analytes of interest are poorly defined Creatinine: large improvements a model? Current PT materials (chemistry) are generally not commutable Need to monitor accuracy/trueness and Accuracy-Based PT materials are important for this 37

104 Summary Achieving accuracy for many chemistry/endocrinology tests is challenging Accuracy based surveys offer direct grading against the true value, not a peer group Logistical impediments to developing ABS products, especially for disease states/levels. 38

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