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Outcome-related test quality

Outcome-related test quality. Linda Thienpont Linda.thienpont@ugent.be. Postgraduaat & navormingsprogramma klinische biologie (29-11-2007) Vernieuwing & evaluatie van kwaliteit van immunoassay doseringen. Overview. Introduction Background Analytical quality – An issue?

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Outcome-related test quality

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  1. Outcome-related test quality Linda Thienpont Linda.thienpont@ugent.be Postgraduaat & navormingsprogramma klinische biologie (29-11-2007) Vernieuwing & evaluatie van kwaliteit van immunoassay doseringen

  2. Overview • Introduction • Background • Analytical quality – An issue? • Outcome-related test quality – • TSH, subclinical hypothyroidism Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  3. Background • Plebani M, Carraro P. Mistakes in a stat laboratory: types and frequency. Clin Chem 1997;43:1348-51. • The distribution of mistakes was: • -pre-analytical 68.2%, • -analytical 13.3%, and • -post-analytical 18.5%. • >Focus on pre- and post-analytics • Critique • Stöckl D. Modern quality management misunderstood? Clin Chem 1998;44:1066-7. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  4. Background • “Analytical errors are no longer the main factor influencing the reliability and clinical utilization of laboratory diagnostics.” • Lippi G, Guidi GC, Mattiuzzi C, Plebani M. Preanalytical variability: the dark side of the moon in laboratory testing. Clin Chem Lab Med 2006;44:358-65. • Is that so? Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  5. Analytical quality • Kidney disease • Calcium • Vitamin D • Parathyroid hormone Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  6. Analytical quality – Calcium • “Based on analysis of over 89,000 patients receiving serum calcium tests at the Mayo Clinic in 1998–1999, we find that the number of follow-up procedures, and hence health care costs, is directly related to initial calcium test values. With approximately 3.55 million patients per year receiving screening serum calcium tests being affected by bias, the potential economic impacts range from $60 million to $199 million per year for analytic biases of 0.1 and 0.5 mg/dL, respectively”. • Gallagher MP, Mobley LR, Klee GG, Schryver P. RTI Planning Report 04-1, The impact of calibration error in medical decision making. April 2004. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  7. Analytical quality – Vitamin D • “Vitamin D assays yield markedly differing results; whether an individual is found to have low or normal vitamin D status is a function of the laboratory used. If the medical community is to make progress in correcting widespread hypovitaminosis D, vitamin D measurement must be standardized” • Binkley N et al. Assay variation confounds the diagnosis of hypovitaminosis D: A call for standardization. J Clin Endocrinol Metab 2004;89:3152–7. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  8. Analytical quality – PTH • “It appears unethical that all the companies making different PTH assays could not meet and decide how to standardize and calibrate a consistent circulating PTH measurement. Many physicians are making huge efforts to keep their patients within the target values recommended by the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/K-DOQI); however, most of them are misinformed by their PTH measurement”. • Torres PU. The need for reliable serum parathyroid hormone measurements Kidney Int 2006;70:240-3. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  9. Analytical quality • “Analytical quality: still a major issue” • “The emphasis on improved quality assessment for pre- and post-analytical processes is not without negative effects.” • “In my view, the only solution to this is to use more stringent metrics to define analytical tolerance limits on the one hand, and on the other to meet the need for more effective communication of laboratory results to clinicians.” • Plebani M. Errors in laboratory medicine and patient safety: the road • Ahead. Clin Chem Lab Med 2007;45:700–7. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  10. Outcome-related test quality • TSH • Subclinical hypothyroidism • “Define analytical tolerance limits” •  interrelated • “Need for more effective communication of results to clinicians” Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  11. TSH – Subclinical hypothyroidism • Information to establish outcome-related test quality • Clinical definition • [Medical] actions • TSH-distribution in the laboratory • Methods to derive "analytical tolerance limits" • At different cut-off values • Modulation of the distribution • Bias • Interferences Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  12. TSH – Subclinical hypothyroidism • Clinical definition • TSH >5 mIU/L • Belgian situation? Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  13. TSH – Subclinical hypothyroidism • [Medical] actions based on values >5 mIU/L • Laboratory tests • Free T4 • Thyroid antibodies • Ultrasonography • Medical actions • Thyroxine supplementation# • #39% of the patients • Fatourechi V, et al. Factors influencing clinical decisions to initiate thyroxine therapy for patients with mildly increased serum thyrotropin (5.1-10.0 mIU/L). Mayo Clin Proc 2003;78:554-60. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  14. TSH – Subclinical hypothyroidism • TSH-distribution in the laboratory (n = 1000) • Modelled according to NHANES III-data (Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab 2005;90:5489-96). Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  15. TSH – Subclinical hypothyroidism • TSH >5 mIU/L • n = 27 (per 1000) • 2.7 % Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  16. TSH – Subclinical hypothyroidism • Methods to derive "analytical tolerance limits" • Modulation of the distribution • Bias • Interferences Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  17. Modulation of the distribution • Bias (at cut-off 5 mIU/L) • A bias of 10% increases the patients to be followed-up by 33% (9 more per 1000 tests). • >Generally considered too much! Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  18. Modulation of the distribution • Interferences • The prevalence of heterophilic antibody interference was determined using thyrotropin as an illustrative example. Serum samples were obtained from 295 patients. Protocol A (zero blocker), protocol B (routine blocker concentration). Ten patients (prevalence 3.4%) had significant levels of heterophilic antibodies (protocol A value greater than 9 SD from the protocol B value).# • #Ward G, McKinnon L, Badrick T, Hickman PE. Heterophilic antibodies remain a problem for the immunoassay laboratory. Am J Clin Pathol 1997;108:417-21. • Després N, Grant AM. Antibody interference in thyroid assays: a potential for clinical misinformation. Clin Chem 1998;44:440–54. • Ismail AAA et al. Wrong Biochemistry Results: Two Case Reports and Observational Study in 5310 Patients on Potentially Misleading Thyroid-stimulating Hormone and Gonadotropin Immunoassay Results. Clin Chem 2002;48:2023–29. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  19. Modulation of the distribution • Interferences (at cut-off 5 mIU/L) • Difficult to translate in real practice. • Assume • 0.1%, 0.5%, 1% of the samples have interferences that cause TSH values to be falsely elevated >5 mIU/L. • 0.5% of samples with interferences increase the patients to be followed-up by 19% (5 more/1000 tests). Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  20. Change of cut-off • Cut-off at 3 mIU/L • 5.4 times more patients to be followed-up (145 instead of 27 per 1000 tests). •  Major impact Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  21. Modulation of the distribution • Bias (at cut-off 3 mIU/L) • A bias of 10% increases the patients to be followed-up by 34% (50 more per 1000 tests). • The %-increase is similar to the 5 mIU/L cut-off, but the absolute numbers are much higher. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  22. Modulation of the distribution • Interferences (at cut-off 3 mIU/L) • 0.5% of samples with interferences increase the patients to be followed-up by 3.4% (5 more per 1000 tests). Note: may be underestimated because the magnitude of interference needed is smaller. •  In a “high prevalence” situation (many values > cut-off), interferences may be less a problem. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  23. 8.3 7.6 Actual bias data from IQC • Target: 7.6 mIU/L • Shift over 2 months • 7.6 > 8.3 = 9.2% ~10% • A bias of +10% increases the patients to be followed-up (FP) by 33%. Acceptable? Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  24. Actual bias data from IQC • Assume 8.3 mIU/L was the target • Shift over 2 months • 8.3 > 7.6 = 8.4% • A bias of -8.4% reduces the patients to be followed-up (FN) by 26%. 8.3 7.6 Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  25. Outcome-related test quality • Observations • Bias and interferences may produce false positives/negatives • How much does a laboratory want to accept? • Follow recommendations in literature • A bias of 10% increases the patients to be followed-up by 33% (9 more per 1000 tests). • Considered too much by Klee GG (Mayo Clinics perform >100 000 TSH measurements per year). • >Risk assessment Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  26. Risk assessment • Risk • = severity times probability (likelihood) • Risk assessment matrix Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  27. Risk assessment • What is the consequence of a false positive? • Additional laboratory testing • Thyroxine supplementation • Are the consequences of a false positive at high, medium, or low risk? • Very difficult to answer • Few models available • >Laboratory may develop basic risk assessment strategies Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  28. Outcome-related test quality • Areas that may be affected • Purchase of equipment • Batch acceptance • IQC • … Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  29. Outcome-related test quality • Possible actions when risk is identified • Intensify communication “Analytics/Clinic” • Purchase a better system • Modify standard practices(examples) • Test batches before use: refuse if possible • Work with IQC rules with increased probability of false positives • Standard practices are understood as: • Practices that are based on the statistics of the stable process and using decisions at the 95% or 99% probability-level (Null-hypothesis) or 90% probability-level (Power calculations). Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  30. TSH – outcome-related test quality • Other references • Klee GG. Clinical interpretation of reference intervals and reference limits. A plea for assay harmonization. Clin Chem Lab Med 2004;42:752-7. • Fatourechi V, Klee GG, Grebe SK, Bahn RS, Brennan MD, Hay ID, McIver B, Morris JC 3rd. Effects of reducing the upper limit of normal TSH values. JAMA 2003;290:3195-6. • Klee GG, Schryver PG, Kisabeth RM. Analytic bias specifications based on the analysis of effects on performance of medical guidelines. Scand J Clin Lab Invest 1999;59:509-12. • Hay ID, Klee GG. Linking medical needs and performance goals: clinical and laboratory perspectives on thyroid disease. Clin Chem 1993;39:1519-24. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  31. Outcome-related test quality • Important only for TSH and similar? Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  32. Outcome-related test quality • Serum sodium • Action limits? • Mild hyponatraemia: <135 - 125 mmol/L • Moderate hyponatraemia: <125 - 115 mmol/L • Severe hyponatraemia: <115 mmol/L • (Smellie WSA, Heald A. Hyponatraemia and hypernatraemia: pitfalls in testing. BMJ 2007;334:473-476) Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  33. Moderate hypo Outcome-related test quality • Serum sodium • Reference population • >would tolerate quite high values for bias Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  34. Moderate hypo Outcome-related test quality • Serum sodium • Distribution of admission serum sodium in patients hospitalized with a primary discharge diagnosis of heart failure. Gheorghiade, M. et al. Eur Heart J 2007;28:980-8. Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  35. Moderate hypo Outcome-related test quality • Serum sodium • Reference population (blue) • >Importance of the real distribution Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

  36. Outcome-related test quality • Summary • Concept becomes increasingly important (own opinion) (alternative or complementary to other concepts, e.g. the biological –) • Engage in the topic • Inform yourself about test quality (ongoing) • Communicate with clinicians • Use data from LIS; do modulations on the basis of bias/interferences, imprecision; investigate [clinical] consequences • Think about risk assessment • Act on “risk analytes” Postgraduaat en navormingsprogramma, UZ Brussel, 29-11-2007

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