Standarization or Standarisation? Harmonization or Harmonisation? We seem to be headed toward a schism in performance specifications, rather than a consensus. Here's a current comparison of Global Performance Specifications for Chemistry Assays.

This article is exclusively sponsored by LGC Technopath Clinical Diagnostics
 

Consolidated Comparison of Chemistry (and Toxicology) Performance Specifications

Sten Westgard, MS

Updated October 10, 2022 with Brazilian criteria. Russian criteria eliminated.
Updated July 24, 2022 with CLIA 2024 proposed proficiency testing criteria
Updated June 12, 2022 with EFLM minimum quality recommendations
Updated February 17, 2022 with 2021 RIQAS state of the art goals
Updated January 21, 2022

There are more and more performance specifications being generated today than there were in existence in the past. A proliferation of all of these goals can result in a lack of coherence in quality. One of the great changes to performance specifications was triggered at the Milan meeting of 2014, (which provided us the resulting consensus statement of 2015) where the authority over the "Ricos goals" was passed from the Spanish EQA societies, over to the EFLM organization, where they are being more rigorously analyzed and organized. The EuBIVAC checklist, which promotes a standard protocol for biological variation studies, has spurred a new series of papers that have significantly re-stated the biological variation-derived analytical performance specifications. While some of those studies specifically calculated allowable analytical total error, others did not. Thus, this table below provides new information not reproduced elsewhere.

[Full credit  must be paid to the the Analytical Quality Commission (CCA) of the Spanish Society of Laboratory Medicine (SEQC^ML), which represents the formal vision, concerning quality items in laboratory medicine, of the Spanish professionals that are federated with the EFLM and then with the IFCC. Without their effort, from 1999 to 2015, the database of biological variation would never have gotten off the ground. You can see a brief and personal review of their history in a recent interview of the EFLM newsletter: https://www.eflm.eu/upload/newsletters/2022-May-Jun-EuroLabNews.pdf ]

We have opted to use both the data from the EuBIVAS studies as well as the EFLM database performance specifications for desirable and minimum quality.

Routine Chemistry Performance Specifications (allowable total analytical error, TEa)
Test or Analyte	Recommended Choice	CLIA	CLIA "2024"[h]	2021 RIQAS SOTA	2014 Desirable "Ricos goals"	EFLM/ Des(f)/ MIN(g) EuBIVAS	Rilibak	RCPA ALP	Brazil	China WS/T 403-2012	2015 "Spanish Min."
Alpha-1 Antitrypsin	± 9.6%		± 20% or positive or negative	±9.6%	± 9.2%	±6.2% [f] ±9.3% [g]
Acid Phosphatase	± 10.3%				± 10.3%
Adinoponectin						±29.1% [f] ±43.7%[g]
Alanine aminotransferase (ALT)	±16.1%	± 20%	± 15% or  ± 6 U/L	±15.1%	± 27.5%	±14.4%[a] ±16.1%[f] ±24.1%[g]	± 21%	± 5 U/L or 12%	± 40%	± 16%	± 23%
Albumin	± 10%	± 10%	± 10%	±9%	± 4.1%	±5.2%[g]	± 20%	± 2.0 g/L or 6%	± 30%	± 6%	± 14%
Alkaline phosphatase	±14.5%	± 30%	± 20%	±18.5%	± 12.0%	±10.7%[a] ±14.5%[f] (bone) ±21.7%[g] (bone) ± 10.5%[f](liver) ±15.8%[g] (liver)	± 21%	± 15 U/L or 12%	± 50%	± 18%	± 31%
Amylase	± 14.6% ± 12.2% (pancreatic)	± 30%	± 10%	±20.3%	± 14.6%	±13.7%[a] ±13.2%[f] ±19.8%[g] ±12.2%panc[f] ±18.3%panc[f]		± 10 U/L or 15%	± 50%	± 14.6%	± 35%
Apolipoprotein A1	± 11.3%				± 9.1%	± 7.6% [f] ± 11.3% [g]		± 0.2 g/L or 10%
Apolipoprotein B	± 11.6%				± 11.6%	± 11.5% [f] ± 17.2% [g]		± 0.2 g/L or 10%
Aspartate aminotransferase (AST)	± 16.7%	± 20%	± 15% or ± 6 U/L	±14.8%	± 16.7%	±13.4%[a] ±13.6%[f] ±20.5% [g]	± 21%	± 5 U/L or 12%	± 30%	±  15%	± 21%
Bilirubin, direct	± 44.5%			±25.8%	± 44.5%	±33.4%[b]		± 3 umol/L or 20%
Bilirubin, total	± 0.4 mg/dL or ± 20%	± 0.4 mg/dL or ± 20%	± 20% or ± 0.4 mg/dL	±15.9%	± 27%	±24.8%[f] ±37.3%[g]	± 22%	± 3 umol/L or 12%	± 0.4 mg/dL or ± 20%	±  15%	± 24%
Blood gas p02		± 3 SD	± 15 mm Hg or ± 15%
Bicarbonate	± 5 mm Hg or ± 8%	± 5 mm Hg or ± 8%	± 20%	±17.3%	± 4.86%	±4.9% [f] ±7.3%[g]		± 2.0 mmol/L or 10%
Blood gas pH		± 0.04	± 0.04		± 3.9%
C-Reactive Protein (CRP)	± 50.7% ± 72.9% (hs)		± 1 mg/dL or 30% (hs)	±8.8%	± 56.6%	± 50.7%[f] ± 72.9% hs [f] ± 76.1%[g] ± 109.4% hs [g]		± 0.8 mg/L or 20%
Calcium, total	± 1.0 mg/dL	± 1.0 mg/dL	± 1.0 mg/dL	±8.3%	± 2.5%	± 2.3%[f] ± 3.4%[g]	± 10%	± 0.10 mmol/L or 4%	± 15%	± 5%
Carbamazepine	± 25%	± 25%	± 20% or ± 1.0 mcg/dL	±11.1%				± 20%
Chloride	± 5%	± 5%	± 5%	±4.6%	± 1.5%	± 1.2% [b] ± 1.3% [f] ± 2.0% [g]	± 8%	± 3.0 mmol/L or 4%	± 13%	± 4%	± 9%
Cholesterol, total	± 10%	± 10%	± 10%	±8.6%	± 9.0%	± 9.3%[d] ± 8.7%[f] ±13.0%[g]	± 13%	± 0.30 mmol/L or 6%	± 15%	± 9%	± 11%
Cholesterol, HDL	± 20%	± 30%	± 20% or ± 6 mg/dL	±21.1%	± 11.6%	±11.1%[d] ±11.1%[f] ±16.6%[g]		± 0.10 mmol/L or 12%	± 30%		± 33%
Cholesterol, LDL	± 20%		± 20%	±20.6%	± 11.9%	±11.3%[d] ±13.7%[f] ±20.5%[g]		± 0.2 mmol/L or 10%
Cholesterinase	± 9.8%			±13.3%	± 9.8%			± 500 U/L or 10%
Complement C3	± 15%		± 15%	±7.9%	± 8.4%	±7.8%[f] ±11.6%[g]
Complement C4	± 16%	± 5 mg/dL or 30%	± 5 mg/dL or ± 20%	± 9%	± 16%	±12.1%[f] ±18.1%[g]
Cortisol	± 22.8%	± 25%	± 20%	±13.5%	± 22.8%	± 26.3%[f] ± 39.4% [g]		± 15 nmol/L or 15%	± 25%
Creatine kinase	±24%	± 30%	± 20%	± 11.3%	± 30.3%	±20.4%[a] ±22.6%[f] ± 33.8%[g]			± 40%	± 15%	± 24%
Creatine kinase isoenzymes		MB elevated (present or absent) or  ± 3 SD Creatinine	± 25% or ± 3 ng/mL  (greater) or MB elevated (presence or absence)
Creatinine	± 0.3 mg/dL or ± 15%	± 0.3 mg/dL or ± 15%	± 0.2 mg/dL or ± 10%	±12.6%	± 8.9%	±6.4%[c] ±7.4%[f] ±11.1%[g]	± 20%	± 8.0 umol/L or ± 8%	± 0.4 mg/dL or ± 20%	± 12%	± 20%
Digoxin	± 0.2 ng/L or ± 20%	± 0.2 ng/L or ± 20%	± 15% or ± 0.2 ng/mL	±14.9%							± 20%
GGT	± 22.1%		± 5 U/L or ± 15%	±17.9%	± 22.1%	±16.2%[a] ±18.9%[f] ±28.3%[g]	± 21%	± 5 U/L or ± 12%	± 40%	± 11%	± 22%
Gentamicin	± 25%	± 25%	± 25%	±13.3%				± 15%
Glucose	± 6 mg/dL or ± 10%	± 6 mg/dL or ± 10%	± 6 mg/dL or ± 8%	±8.5%	± 7%	± 6.3%[e] ± 6.5%[f] ± 9.8%[g]	± 15	± 0.4 mmol/L or ± 8%	± 13%	± 7%	± 12%
HbA1c (NGSP)	± 6.0% [NGSP]		± 8.0%			±2.8%[e] ±2.2%[f] ±3.3%[g]
HbA1c (IFCC)	± 3.1% [IFCC]					± 3.1% [f] ± 4.7% [g]
Haptoglobin	± 27.3%			±7.9%	± 27.3%	± 17.1%[f] ± 25.6% [g]
IgA	± 14.7%		± 20%	±7.9%	± 13.5%	± 9.8%[f] ±14.7%[g]		± 25%			± 21%
IgG	± 20%		± 20%	±7.9%	± 8%	± 7.3%[f] ±10.9%[f]		± 25%			± 16%
IgM	± 28%		± 20%	±7.9%	± 16.8%	± 17.1%[f] ±25.6%[g]		± 25%			± 28%
Iron, total	± 15%	± 20%	± 15%	±10%	± 30.7%	± 26.7%[f] ± 40.0%[g]		± 30%	± 29%	±  15%	± 24%
Lactate	± 30.4%			±9.1%	± 30.4%	±36.2%[e]		± 0.2 mmol/L
Lactate dehydrogenase (LDH)	± 15.0%	± 20%	± 15.0%	±12.8%	± 11.4%	±7.7%[f] ±11.5%[g]	± 18%	± 40%	± 22%	± 11%	± 26%
LDH isoenzymes		LDH1/LDH2 (+ or -) or ± 30%
Lipase	± 37.9%			±25.7%	± 37.9%	±12.6%[a] ±14.2%[f] ±21.3%[g]	± 25%
Lipoprotein (a)						±9.35%[f]
Lithium	± 15%	± 0.3 mmol/L or 20%	± 15% or ± 0.3 mmol/L	±11.7%				± 0.3 mmol/L or 30%			± 18%
Magnesium	± 25%	± 25%	± 15.0%	±11%	± 4.8%	±4%[b] ±4.0[f] ±6.0%[g]	± 15%	± 25%	± 13%	± 15%
Osteocalcin	± 15.7%					±15.7[f] ±23.6%[g]
Phenobarbital	± 20%	± 20%	± 15% or ± 2 mcg/mL	±13.7%				± 20%			± 15%
Phenytoin	± 25%	± 25%	± 2 mcg/dL  or 15%	±14.6%				± 20%			± 13%
Phosphorous	± 10.1%		± 0.3 mg/dL  or 10%		±10.1	± 9.7%[f] ± 14.6%[g]		± 20%			± 17%
Potassium	± 0.3 mmol/L	± 0.5 mmol/L	± 0.3 mmol/L	±5.6%	± 5.6%	±4.6%[b] ±4.8%[f] ±7.3%[g]	± 8%	± 0.5 mmol/L	± 9%	± 6%	± 8%
Prealbumin	± 14.5%			±9.4%	± 14.5%
Prolactin	± 37.4%					±37.4%[f] ±56.1%[g]		± 20%
S100 calcium-binding protein B	± 17.0%					±17.0%[f] ±25.5%[g]
Salicylate	± 15.0%		± 15% or ± 2 mcg/dL
Sodium	± 4 mmol/L	± 4 mmol/L	± 4 mmol/L	±3.6%	± 0.7%	±0.7%[f] ±1.0%[g]	± 5%	± 8 mmol/L	± 4%	± 4%	± 5%
Theophylline	± 25%	± 25%	± 20%	±9.9%				± 25%
Tobramycin	± 25%	± 25%	± 20%	±9.4%				± 25%
Total protein	± 10%	± 10%	± 8.0%	±8.7%	± 3.6%	± 3.4%[b] ± 3.5%[f] ± 5.2%[g]	± 10%	± 12%	± 9%	±  5%	± 12%
Transferrin	± 20%			±7.9%	± 3.8%	±6.8%[f] ±10.2%[f]
Triglycerides	± 25%	± 25%	± 15%	±15.4%	± 26%	±28%[d] ±27.0%[f] ±40.6%[g]	± 16%	± 16%	± 33%	± 14%	± 18%
Urea Nitrogen	± 2 mg/dL or ± 9%	± 2 mg/dL or ± 9%	± 2 mg/dL or ± 9%	±12.5%	± 15.5%	±16.1%[b] ±17.8%[f] ±26.6%[g]	± 21%	± 18%	± 22%	± 8%	± 19%
Uric acid	± 17%	± 17%	± 10%	±10.6%	± 12%	±10.6%[b] ±12.8%[f] ±19.2%[g]	± 13%	± 15%	± 18%	± 12%	± 17%
Valproic Acid	± 25%	± 25%	± 20%	±12.1%				± 20%
Vancomycin	± 2 mcg/dL or 15%		± 2 mcg/dL or 15%	±16.2%				± 25%
25-hydroxy vitamin D	± 25%			±22.4%		±12.4%[f] ±18.7%[g]		± 5 ng/mL or 25%

This is not an exhaustive list of goals. Indeed, RCPA goals and other popular goals are available on other pages on the website here. But this gives an idea of the global range of goals. There are some large disparities, and we will use the rest of 2019 to explore the implications of these differences and the challenges that laboratory performance will face if we adopt all of the new EFLM specifications.

Here are the references for the EuBIVAS studies:

a. Biological Variation Estimates Obtained from 91 Healthy Study Participants for 9 Enzymes in Serum, Carobene A, Roraas T, Solvik UO, et al, Clin Chem 63:6. 2018.

b. EuBIVAS: Within- and Between-Subject Biological Variation Data for Electrolytes, Lipids, Urea, Uric Acid, Total Protein, Total Bilirubin, Direct Bilirubin, and Glucose, Aarsand AK, Diaz-Garzon J, Fernandez-CAlle P et al, Clin Chem 64:9 2017

c. The EuBIVAS Project: Within- and Between-Subject Biological Variation Data for Serum Creatinine Using Enzymatic and Alkaline Picrate Methods and Implications for Monitoring, Carobene A, Marino I, Coskun A et al, Clin Chem 63:9. 2017 Estimates from Enzymatic methods used.

d. Biological variation data for lipid cardiovascular risk assessment biomarkers. A systematic review applying the biological variation data critical appraisal checklist (BIVAC), Diaz-Garzon J, Fernandez-CAlle P, Minchinel J et al Clin Chim Acta 495 (August 2019) 467-475.

e. Systematic review of the biological variation data for diabetes related analytes, Gonzalez-Lao E, Corte Z, Simon M et al, Clin Chim Acta 488 (January 2019) 61-67.

f. EFLM database, originally accessed 1/13/2020. most recently updated with SIMED assistance 1/20/22 https://biologicalvariation.eu/meta_calculations

g. EFLM database, originally accessed 1/13/2020. most recently updated with new MINIMUM quality recommendations 6/12/22 https://biologicalvariation.eu/meta_calculations

 h. CLIA 2024 proficiency testing criteria, quoted from the Federal Register Vol 87, No 131, July 11, 2022. Full listing at https://www.westgard.com/2024-clia-requirements.htm

[Thanks to Randox RIQAS for sharing their State of the Art (SOTA) goals from their monthly EQA program]

[Special thanks to Vladimir Procenko, for an informal English translation of the Russia GOST goals, of which Annex A is listed here, which represents the maximum allowable analytical error for a single measurement.]