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B e s t p r a c t i c e s f o r q u a l i t y c o n t r o l a n d i n t e r - l a b o r a t o r y s t a n d a r d i z a t i o n
o f b i o m a r ke r r e s u l t s i n t h e c l i n i c a l c h e m i s t r y l a b o r a t o r y
R a d b o u d v a n T r i g t , P R A H e a l t h S c i e n c e s1 8 S e p t e m b e r 2 0 1 9
2P R A H E A L T H S C I E N C E S
S i e m e n s C l i n i c a l C h e m i s t r y A n a l y z e r • Urinalysis• Biochemistry• Serology• Hematology• Coagulation• Hormones• Protein analyses• Biomarkers, e.g.
• Aldosterone• Cortisol• Estradiol• PTH• FSH• hCG• NT-proBNP• SHBG• TNF-α• VwF
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I n t r o d u c t i o n C l i n i c a l C h e m i s t r y H a r m o n i z a t i o n
§ Since early 1970s: Harmonization of results between laboratories, irrespective of ….. § Location§ Technology§ Manufacturer§ Timing
§ Data are used in clinical decision making (accurate and actionable data needed)
§ A systematic approach is needed due to the complexity of harmonization§ Standardize collection procedures§ Organize inter-laboratory comparisons§ Normalize sample outcomes based on this comparison (?) § Determination of reference intervals
§ Traceable common reference system needed: measurement accuracy is important
4P R A H E A L T H S C I E N C E S
R e f e r e n c e R a n g e
§ What is a healthy normal and what is suspected?§ Described in literature
§ Biological variation§ Age§ Sex§ Race§ Body weight, …….§ Other disease
§ Laboratory dependent§ Target population§ Location
§ At PRA this is a non-typical population. Yearly evaluation for trends to evaluate the need to adjust reference range
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R e f e r e n c e R a n g e
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S o d i u m
§ Biochemical analysis, serum
§ Siemens Advia Chemistry XPT
§ 15,000 samples analyzed per year at PRA
§ Method: Ion Selective Electrode, indirect
§ Literature Range: 135 – 145 mmol.L-1
§ Reference Range PRA: 135 – 145 mmol.L-1
§ Calibration of electrode, no calibration curve
§ 3 (multicomponent) QC levels; 3 times a day§ Acceptance: measured value +/- SD§ New QCs are bridged over 1 month (daily)
7P R A H E A L T H S C I E N C E S
E x t e r n a l Q u a l i t y A s s u r a n c e S e r v i c e s ( E Q A S )
§ Sodium in human serum§ Murex EQAS, Biorad: use of large peer groups§ Monthly, single sample
§ Lyophilized, human serum based
§ Part of large clinical chemistry panel (49 analytes)§ http://www.bio-rad.com/en-nl/product/eqas-clinical-chemistry-monthly-
program?ID=3a1e7177-498f-4e12-a392-2ef6853088dd
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E Q A S B i o r a d , S o d i u m – S a m p l e 1 1
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E Q A S B i o r a d , S o d i u m – Z - s c o r e s
10P R A H E A L T H S C I E N C E S
S K M L
§ Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek§ Dutch system§ Partially overlapping with Biorad Murex
§ https://www.skml.nl/rondzendingen/overzicht/rondzending?id=1
§ Every 2 months, 6 samples per round
§ 29-panel (“Combi Algemene chemie”)
ALAT Albumin Alk. Phosphatase Ammonia AmylaseASAT Bilirubin Bilirubin direct Calcium ChlorideCK Creatinine eGFR (F, 55,
white)Gamma-GT Glucose
Inorg. Phosphate Iron Lactate LD Lipase
Lithium Magnesium Osmolality Potassium Pseudo Cholinesterase
Sodium Total Protein Urate Urea
11P R A H E A L T H S C I E N C E S
S K M L f o r S o d i u m
§ Sample A and E
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S K M L f o r s o d i u m
13P R A H E A L T H S C I E N C E S
H e m o g l o b i n
§ Siemens Advia 2120i Hematology
§ Method:§ Red blood cell lysis, oxidation iron, colorimetric read out
§ 15,000 samples analyzed per year at PRA
§ Literature Range:§ Females: 7.5 – 10.0 mmol.L-1
§ Males: 8.5 – 11.0 mmol.L-1
§ Reference Range PRA:§ Females: 7.2 – 9.6 mmol.L-1
§ Males: 8.3 – 10.8 mmol.L-1
§ Periodic calibration of the instrument
§ SKML: Every 2 months, 8 fresh whole blood samples
14P R A H E A L T H S C I E N C E S
S K M L f o r H e m o g l o b i n
§ Sample A and E
15P R A H E A L T H S C I E N C E S
S K M L f o r H e m o g l o b i n
16P R A H E A L T H S C I E N C E S
R e g u l a t i o n s f o r C l i n i c a l C h e m i s t r y L a b o r a t o r i e s
§ ISO 15189 for laboratory medicine (based on ISO 17025)§ Quality Management System for entire chain (including pre-analysis)§ Not very specific: scientific freedom on execution
§ Clinical Laboratory Improvement Amendments (CLIA) for human diagnostics and prognostics§ US-based system§ Accreditation§ External proficiency testing§ Accuracy, reliability and timeliness of test results§ College of American Pathologists (CAP) accreditation may be added: peer-based review
§ Instruments must be validated (CSV)
§ Guidelines do not guarantee good science
§ Biological variation, reference databases:§ Westgard: https://www.westgard.com/biodatabase1.htm§ CLSI: https://clsi.org/
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F u l l V a l i d a t i o n i n a C l i n i c a l C h e m i s t r y L a b o r a t o r y S e t t i n g
§ Full validation can be organized using a CCL assay. However, ……..§ What is considered a run?§ Should a calibration curve be spiked?
§ In matrix§ Source of standard material and characterization
§ QCs in every “run” rather than 3 times per day?§ Endogenous or spiked
§ Stability tests need to be added
§ Full validation for a biomarker can be performed, but with adaptations (like for any biomarker assay)
§ Advantages§ Quality consistent over time§ Often tight CVs§ Turnaround time§ Costs
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B i o a n a l y t i c a l L a b o r a t o r i e s
§ Do we also need harmonization between assays in bioanalysis?§ Is there a need to compare data between studies?§ Do we need to compare data with literature?
§ Which biomarkers should be considered for harmonization?
§ Who should organize this process?
§ We can start by harmonizing within a clinical development program (or pharma company)§ Longitudinal endogenous assay controls§ Share those data across laboratories?§ What to do with that information?§ Who should take the lead?
19P R A H E A L T H S C I E N C E S
A c k n o w l e d g e m e n t s
§ Geert Sloots
§ Nico van de Merbel
§ Chad Briscoe
§ Jacomijn Dijksterhuis
§ Martine Broekema
§ And many more PRA staff members
