Four rules to remember: 1) Addition, subtraction, multiplication and division of SD and/or CV.

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1 Analytical Quality Specifications for Thyroid Hormones Bayer Nordic Users Meeting, 17. September Frode Engbaek, Ph. D., Department of Clinical Biochemistry, Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark Four rules to remember: 1) Addition, subtraction, multiplication and division of SD and/or CV. For additions and subtractions: c = a ± b SD 2 c = SD 2 a + SD 2 b Coefficient of variation is the relative SD : CV = SD / mean % For multiplications and divisions, if CV < 10 %: c = a x b or c = a / b CV 2 c = CV 2 a + CV 2 b 2) Standard error of the mean: SEM 2 = SD 2 /n or 3) An 1,12 fold increase in SD is small and acceptable. 4) The reference interval is: Total biological variation + analytical variation.

2 Analytical Quality Specifications for Thyroid Hormones Page 2 Who decide analytical quality specifications? 1) Laboratory QC manager 2) Patients or human biology 3) External Quality Assessment Scheme managers 4) Manufacturer Analytical quality specifications from a QC-manager s point of view: Goal: Long term stable decision limits for internal controls. Problems: New lot of reagent:

3 Analytical Quality Specifications for Thyroid Hormones Page 3 New lot of calibrator:

4 Analytical Quality Specifications for Thyroid Hormones Page 4 How to minimize the effect of variations in calibrations. SD 2 result = SD 2 sample + SD 2 calibrator If calibration is perform with single determinations: SD calibration = SD sample SD 2 result = 2 x SD 2 sample or SD result = 1,41 x SD sample The influence of calibration can be diminished, if calibration is performed with multiple determinations: SD 2 result = SD 2 sample + SEM 2 calibrator If calibration is performed in quadruplicate determinations: SD 2 result = SD 2 sample + SD 2 sample / 4 = 1,25 x SD 2 sample SD result = 1,118 x SD sample, and this is a small and acceptable increase in the SD (rule 3) Which SD to choose? Problem: SD has a natural variation due to statistical events. Solution: I use 1,00-1,12 x SD controls based upon measurements after values outside ± 3 SD have been removed. When a new batch of control is used, I use the SD or CV from the old batch. Clinical problems: 1) P-TSH, measured October 2000: 1,00 mu/l P-TSH, measured April 2001: 1,20 mu/l Is the change due to biological variation or analytical variation? 2) P-TSH, measured August 2001 at Aarhus Kommunehospital: 1,00 mu/l P-TSH, measured September 2001 at Aarhus Amtssygehus: 1,20 mu/l Is the change due to biological variation or analytical variation? Do the two hospitals have different bias? Analytical quality specifications for patients needs. Analytical precision (CV): Optimum: 0,00-0,25 x CV of intraindividual variation Desirable: 0,25-0,50 x CV of intraindividual variation Minimum: 0,50-0,75 x CV of intraindividual variation Analytical bias: Optimum: 0,000-0,125 x CV of total biological variation Desirable: 0,125-0,250 x CV of total biological variation Minimum: 0,250-0,375 x CV of total biological variation

5 Analytical Quality Specifications for Thyroid Hormones Page 5 Evaluation of analytical variations: Data from internal control: Bio-Rad Immunoassay Plus Control

6 Analytical Quality Specifications for Thyroid Hormones Page 6 Evaluation of analytical variations: Analyses Intraindividual variation, CV % 1 Analytical variation, CV % Ratio and Evaluation P-T3 13,7 5,6 at 2,2 nmol/l 0,41 Desirable P-T4 10,1 7,4 at 90 nmol/l 0,73 Minimum P-TSH 38,5 5,4 at 0,5 mu/l 0,14 Optimum 1 Data obtained from S. Andersen, K. M. Pedersen, I. Bülow, and P. Laurberg, Department of Medical Endocrinology, Aalborg Sygehus, Denmark Informations about biological variations are posted on these sites:

7 Analytical Quality Specifications for Thyroid Hormones Page 7 Evaluation of analytical bias: If analytical variation is small compared to the width of the reference interval: SD total biological variation = 1/4 x width of reference interval Data from external controls (UKNEQAS). The limits shown are 95 % limits = 2 X CV limits. Evaluation of analytical biases: Analyses Reference interval Total biological variation, SD Total biological variation, CV, % Our bias, % from UKNEQAS Ration and Evaluation P-T3 1,1-2,5 nmol/l 0,35 nmol/l 19,4 +0,3 0,015 Optimum P-T nmol/l 20 nmol/l 20,0-1,8 0,090 Optimum P-TSH 0,1-4,0 mu/l 0,975 mu/l 47,6 +5,8 0,122 Optimum

8 Analytical Quality Specifications for Thyroid Hormones Page 8 Analytical quality specifications from UKNEQAS. Analytical variation (VAR) Analyses Intraindividual variation, CV % UKNEQAS acceptable limits for acceptable performance, CV % Ratio and Evaluation P-T3 13,7 7,5 0,55 Minimum P-T4 10,1 5 0,495 Desirable P-TSH 38,5 6,25 0,16 Optimum Analytical quality specifications from UKNEQAS. Analytical variation (BIAS) Analyses Total biological variation, CV % UKNEQAS acceptable limits for acceptable performance, CV % P-T3 19,4 7,5 Ratio and Evaluation 0,387 Worse than minimum P-T4 20,0 5,0 0,25 Desirable P-TSH 47,6 6,25 0,131 Desirable The UKNEQAS limits are determined from the state of the art, not human biology. Analytical quality specifications from manufacturer: 1) Mechanics: Pipetting, timing. 2) Wetware: Reproducibility, stability. This document is posted on the internet at the address: