Scand J Clin Lab Invest 1999; 59: 491 ± 500

Current databases on biological variation: pros,

cons and progress
C. RIC OÂ S , V. A L V A R EZ, F. C A V A , J . V . G ARCIÂ A -L A R I O, A . H E R N AÂ NDEZ,
C. V. JIMEÂ N E Z , J . M I N C H I N E L A , C. PE R I C H & M . S I M OÂ N
Analytical Quality Commission from the Spanish Society of Clinical Chemistry and Molecular
Pathology (SEQC), Spain
Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Hong Kong on 06/06/13

RicoÂs C, Alvarez V, Cava F, GarcõÂa-Lario JV, HernaÂndez A, JimeÂnez CV,

Minchinela J, Perich C, SimoÂn M. Current databases on biological variation:
pros, cons and progress. Scand J Clin Lab Invest 1999; 59: 491±500.

A database with reliable information to derive de®nitive analytical quality

speci®cations for a large number of clinical laboratory tests was prepared in this
work. This was achieved by comparing and correlating descriptive data and
relevant observations with the biological variation information, an approach
that had not been used in the previous efforts of this type. The material compiled
in the database was obtained from published articles referenced in BIOS,
For personal use only.

CURRENT CONTENTS, EMBASE and MEDLINE using ``biological

variation & laboratory medicine'' as key words, as well as books and doctoral
theses provided by their authors. The database covers 316 quantities and reviews
191 articles, fewer than 10 of which had to be rejected. The within- and between-
subject coef®cients of variation and the subsequent desirable quality speci®ca-
tions for precision, bias and total error for all the quantities accepted are
presented. Sex-related strati®cation of results was justi®ed for only four
quantities and, in these cases, quality speci®cations were derived from the
group with lower within-subject variation. For certain quantities, biological
variation in pathological states was higher than in the healthy state. In these
cases, quality speci®cations were derived only from the healthy population (most
stringent). Several quantities (particularly hormones) have been treated in very
few articles and the results found are highly discrepant. Therefore, professionals
in laboratory medicine should be strongly encouraged to study the quantities for
which results are discrepant, the 90 quantities described in only one paper and
the numerous quantities that have not been the subject of study.
Key words: Analytical quality speci®cations; bias; biological variation; database;
precision

C. RicoÂs, Biochemistry Department, Vall d'Hebron General Hospital, Vall

d'Hebron 119, ES-08035 Barcelona, Spain

IN T R O D U C T I O N in clinical laboratories for general purposes,

such as screening, case-®nding, diagnosis and
Models based on biological variation provide monitoring. The components of biological
well-accepted bases for deriving quality goals variation, expressed in percentages, are the
491
 492 C. RicoÂs et al.
within-subject (CVw) and the between-subject
(CVb) variation.
Many works have estimated the biological
variation components and four compilations of
results of biological variation have been pre-
sented: Ross [1], Fraser [2, 3] and SebastiaÂn-
Gambaro et al. [4]. In 1992, the European
Group for the Evaluation of Reagents and
Analytical Systems in Laboratory Medicine
(EGELAB) published quality speci®cations for
imprecision and bias (at that time termed
``inaccuracy'') for 34 quantities [5]. The Spanish
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Society of Clinical Biochemistry and Molecular
Pathology (SEQC) has recommended quality
speci®cations for imprecision, bias, bias in
alternative sites and total error for 50 serum
and urine quantities [6]. The quality speci®ca-
tions in these works were derived from data
on biological variation; however, they were
obtained by averaging the published data
without assessing the reliability of this available
information.
The aim of the present work was to prepare a
database with reliable information that could be
used to derive de®nitive quality speci®cations
For personal use only.
for precision, bias and total error for a large
number of clinical laboratory tests. This was
achieved by comparing and correlating descrip-
tive data and relevant observations with the
biological variation information, an approach
that has not been used in the previous efforts of
this type.
MATERIAL AND METHODS
The information compiled in the database was
obtained from published articles referenced in
BIOS, EMBASE, MEDLINE and CURRENT
CONTENTS, using ``biological variation &
laboratory medicine'' as key words, as well as
books and doctoral theses provided by their
authors.
The information retrieved was classi®ed into
four categories:
1. The components of biological variation, CVw
and CVb, and the analytical imprecision
(CVa);
2. Calculations carried out from the data
appearing in each paper, such as the index
of individuality (II, the ratio of the within-
subject to between-subject variation), refer-
ence change value (RCV, difference between
two consecutive measurements of one ana-
lyte in a person and representing a signi®cant
change in health status), number of speci-
mens needed to establish the homeostatic set
point, and index of heterogeneity (ratio
between the observed CV of a set of
individual variances to the theoretical CV)
[7];
3. Descriptive information such as mean, stan-
dard deviation and units of measurement
obtained for each population studied in each
article, total number of subjects included and
strati®ed by sex when available, period of
time covered (also expressed in days),
number of samples obtained for each subject
studied, model used by each for calculating
the analytical coef®cient of variation, values
of between-run and within-run analytical
precision, numerator of the individuality
index used by the author, type of population
studied, health status, year of publication,
®rst author and journal of publication;
4. Relevant observations which could affect the
estimation of the components of biological
variation, such as fasting conditions and type
of pathology affecting the subjects studied.
A scoring system, based on factors that could
most in¯uence the calculation of the compo-
nents, was designed to delineate the reliability
of the estimates obtained from the published
information.
A. The ratio of the analytical CV and half of
the within-subject CV (index of ®duciability, IF)
[8] was calculated for each article.
B. The mathematical model (MM) used by
the authors to estimate the components of
biological variation was classi®ed into four
groups, according to the following criteria of
decreasing robustness.
. Group 4: works that used nested ANOVA to
assess the components of biological variation;
. Group 3: works that calculated the compo-
nents by manual methods (simple formulae)
described by Fraser & Harris [7];
. Group 2: works that produced data on
within-subject, between-subject and analytical
CV, but with no clear description of methods
used for deriving such data;
. Group 1: works that did not apply the widely
accepted protocols.

For each analyte, all articles having If w2
and/or classi®ed in MM group 1 were initially
considered to be suitable for exclusion in the
®nal evaluation. Articles with other scores were
included.
Information from all eligible articles was
subsequently evaluated on the basis of their
CVw values. These ®gures were arranged in
ascending order and inspected for evident
tendencies that would indicate relationships
with other data ®elds (e.g. study period, sex
of participants, health status, fasting condition).
Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Hong Kong on 06/06/13
When such relationships were found, these
articles were separated from the general evalua-
tion and their CVw and CVb were calculated
individually.
When there were no trends requiring separa-
tion of articles into groups, the medians of the
within- and between-subject CV from all the
articles referring to the speci®c analyte were
calculated to determine the quality speci®ca-
tions.
Desirable quality speci®cations for precision
(I), bias (B) and total error (TE) were calculated
using the following formulae:
For personal use only.
Iv0.5CVw
Bv0.25 (CVw2zCVb2)c
TEv1.65IzB (av0.05)
TEv2.33IzB (av0.01).
RES UL TS
The database covers 316 quantities (determined
in serum, urine, plasma, cerebrospinal ¯uid and
blood) and reviews 191 articles written by 173
authors from 15 countries appearing in a total
of 40 scienti®c journals. fewer than 10 articles of
the total were refused. Of the 316 quantities
studied, 266 appeared in fewer than 10, and 50
in more than 10 articles, with serum cholesterol,
triglycerides and high-density lipoprotein
(HDL)-cholesterol being the most frequently
studied.
To illustrate the information that was
obtained from the database, the data for
cholesterol (Table I) and other quantities
revealed that works using a study period of
less than 1 day obtained the lowest CVw values.
It was considered that the study design in these
works had caused a bias in the results and,
Current databases on biological variation 493
therefore, the estimations of components from
these articles were considered unsuitable for
deriving quality speci®cations.
Another example in which separate trends
were observed was in results from serum
creatinine. There were clear differences between
data from healthy subjects and data from
patients suffering different pathologies. In
these cases estimates of biological variation
were obtained from the group of healthy people
to derive quality speci®cations.
Table II shows the desirable quality speci®ca-
tions for precision, bias and total error for all of
the quantities accepted from the bibliography
studied.
D ISCU SSION
This work focused on establishing de®nitive
analytical quality speci®cations for clinical
laboratories, but the database can be used for
other purposes, such as establishment of delta
checks, promoting common reference change
values and determining individuality of quan-
tities.
The following ®ndings are highlighted.
. The CVw and CVb from articles included in
groups 4 and 3 (according to the mathema-
tical model used) are very similar, demon-
strating the robustness of the formula
proposed by Fraser & Harris [7], which was
used by the majority of authors studied.
. Sex-related strati®cation of results was justi-
®ed for only four quantities and, in these
cases, quality speci®cations were derived from
the group with lower within-subject variation.
. For certain quantities, biological variation in
pathological states was higher than in the
healthy state. In these cases, quality speci®ca-
tions were derived only from the healthy
population (most stringent).
Reliable information regarding biological
variation is presently available for the majority
of the 316 analytes reviewed. The main
advantage of this database is that the authors
were able to determine which articles provided
reliable and which provided poor estimates of
the components of biological variation. The aim
was to avoid the estimation of quality speci®ca-
tions derived from incomplete sources of
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For personal use only.

TABLE I. S-cholesterol.
494

CVw CVb CVa II Nspec IF Mean Units n n (sex) Time Days S/S CVa types MM Year State

3.4 3.1 4 1.8 mmol/l 11 11 0.5 h 0.0208 4 WR 3 1974 H

3.5 5.7 7 3.2 11 11 8h 0.33
2.5 2.9 3 2.3 5.2 mmol/l 28 28 (M) 1d 1 4 BR 1 1982 H
1.5 2.9 2 3.8 5.4 mmol/l 14 14 (F) 1d 1 4 BR 1 1982 H
C. RicoÂs et al.

3.6 2.9 4 1.6 4.4 mmol/l 11 11 (F) 1d 1 4 BR 1 1982 H

2.8 1.8 2 1.3 4.6 mmol/l 62 62 1d 1 4 WR 3 1985 H
4.4 1.6 4 0.7 5.21 mmol/l 25 25 1d 1 6 3 1990 H
2.4 1 5.8 mmol/l 11 11 1d 1 5 4 1990 H
3.9 2.2 4 1.1 10 10 5d 5 3 BR, trip 2 1980 H
6.0 19.0 1.3 0.32 6 0.4 mg/dl 10 10 5d 5 5 BR 3 1989 H
4.8 1.3 4 0.5 4.8 mg/dl 51 51 5d 5 3 BR 2 1990 H
3.7 10.2 4.3 0.36 5 2.3 4.6 mmol/l 5 5 (F) 5d 5 5 WR, dup 4 1992 H
4.3 2.3 4 1.1 20 20 1 w 7 2 BR 4 1988 H
5.1 4 25 1 w 7 WR, dup 3 1989 H
4.8 19.5 0.25 4 14 14 1.4 w 9.8 6 2 1976 H
5.3 11.4 3.1 0.46 6 1.2 4.5 mmol/l 11 11 2 w 14 5 WR, dup 3 1974 H
5.2 1.7 5 0.7 5.0 mmol/l 10 10 (M) 4 w 28 7 WR, dup 3 1987 P
5.2 1.7 5 0.7 5.0 mmol/l 10 10 (F) 4 w 28 7 WR, dup 3 1987 P
4.7 2.0 5 0.9 232.0 mmol/l 35 35 (M) 4 w 28 4 BR 1 1996 P
4.4 15.2 1.7 0.29 4 0.8 10 10 4 w 28 4 WR, dup 3 1978 H
7.1 2.3 9 0.6 mmol/l 20 20 4 w 28 4 BR, dup 3 1990 H
4.2 1.0 3 0.5 5.8 mmol/l 11 11 4 w 28 4 BR 4 1990 H
4.8 2.9 5 1.2 mmol/l 28 28 (M) 1m 30 8 BR 1 1982 H
6.8 2.9 9 0.8 mmol/l 14 14 (F) 1m 30 8 BR 1 1982 H
7.7 2.9 11 0.8 mmol/l 11 11 (F) 1m 30 8 BR 1 1982 H
5.1 4.6 8 1.8 2.0 g/l 83 83 1m 30 3 WR 3 1996 H
4.2 1.8 4 0.9 1.9 g/l 83 83 2m 31 3 WR 3 1997 H
4.2 9.0 3.0 0.47 5 1.4 40 40 3±6 w 32
8.3 17.4 6.3 0.48 17 1.5 4.4 mmol/l 5 5 (F) 5 w 35 5 WR, dup 4 1992 H
3.6 15.1 1.0 0.24 3 0.6 10 10 5 w 35 5 WR 2 1993 H
7.8 2.7 11 0.7 4.5 mmol/l 13 13 5 w 35 20 WR Various 1994 H
7.8 2.5 11 0.6 mmol/l 17 17 (M) 60 w 42 5 WR, dup 1 1979 H
6.7 2.5 8 0.7 mmol/l 11 11 (F) 60 w 42 5 WR, dup 1 1979 H
7.2 1.68 9 0.5 5.6 mmol/l 16 16 (M) 8 w 56 8 WR, dup 3 1987 P
7.5 1.68 10 0.4 5.6 mmol/l 11 11 (F) 8 w 56 8 WR, dup 3 1987 P
7.0 1.70 8 0.5 6.0 mmol/l 14 14 (M) 8 w 56 8 WR, dup 3 1988 P
4.2 1.1 3 0.5 41 41 8 w 56 WR, dup 1 1987 H
4.8 1.68 4 0.7 4.5 mmol/l 10 10 (M) 8 w 56 8 WR, dup 3 1987 H
4.4 1.68 4 0.8 4.6 mmol/l 14 14 (F) 8 w 56 8 WR, dup 3 1987 H
 Scand J Clin Lab Invest Downloaded from informahealthcare.com by University of Hong Kong on 06/06/13
For personal use only.

4.8 1.70 4 0.7 4.5 mmol/l 10 10 (M) 8w 56 8 WR, dup 3 1988 H

5.3 0.7 5 0.3 1.9 g/l 20 20 8w 56 4 3 1994 H
4.2 3.7 5 1.8 16 16 8w 56
7.9 17.9 2.0 0.44 11 0.5 5.2 mmol/l 1105 1105 8.5 w 59.5 9 BR 2 1978 H
7.5 4.0 12 1.1 1061 1061 (M) 2m 60
6.6 4.0 10 1.2 611 611 (F) 2m 60
4.2 13.9 4.9 0.30 7 2.3 204.1 mg/dl 9 9 10 w 70 10 BR, dup 3 1971 H
5.4 1.8 6 0.7 191.0 mg/dl 11 11 10 w 70 10 BR, quat 3 1976 H
5.0 2.0 5 0.8 6.2 mmol/l 128 128 10 w 70 3 BR, dup 3 1992
5.0 2.0 5 0.8 6.2 mmol/l 128 128 10 w 77 3 BR, dup 3 1992 P
6.5 13.6 3.9 0.48 9 1.2 205.0 mg/dl 34 34 (M) 16 w 112 11 BR, dup 3 1970 H
5.9 18.3 3.9 0.32 8 1.3 205.0 mg/dl 34 34 (F) 16 w 112 11 BR, dup 3 1970 H
8.7 4.6 15 1.1 10 10 19 w 133
4.1 13.0 5.7 0.32 8 2.8 11 11 15 w 135
5.8 11.0 1.9 0.53 6 0.7 6.3 mmol/l 27 27 20 w 140 10 WR, dup 4 1989 H
7.9 17.6 4.0 0.45 13 1.0 4.7 mmol/l 5 5 (F) 5m 150 5 WR, dup 4 1992 H
6.0 1.8 7 0.6 5.4 mmol/l 148 148 (M) 6m 180 6 WR 3 1985 H
7.2 1.8 9 0.5 5.4 mmol/l 126 126 (F) 6m 180 6 WR 3 1985 H
8.2 19.5 2.5 0.42 12 0.6 mg/l 44 44 (F) 6m 180 3 WR 3 1990 H
9.3 19.4 1.0 0.48 14 0.2 5.1 mmol/l 26 26 6m 180 8 WR, dup 3 1997 H
7.2 8 85 85 (M) 1 y 365 4 1 1987 P
6.2 1.8 7 0.6 194.0 mg/dl 11 11 12 m 365 19 BR, quat 3 1976 H
6.1 2.9 7 0.9 mmol/l 28 28 (M) 12 m 365 12 BR 1 1982 H
7.3 2.9 10 0.8 mmol/l 14 14 (F) 12 m 365 12 BR 1 1982 H
6.2 2.9 8 0.9 mmol/l 11 11 (F) 12 m 365 12 BR 1 1982 H
6.6 12.6 1.7 0.52 8 0.5 5.2 mmol/l 20 20 1 y 365 12 BR 3 1989 H
7.4 14.6 0.51 9 14 600 14 600 12 m 365 1 1990 H
7.0 15.4 0.9 0.45 8 0.3 5.3 mmol/l 23 23 (M) 12 m 365 13 WR 3 1992 H
7.0 9.9 0.9 0.71 8 0.3 5.1 mmol/l 19 19 (F) 12 m 365 13 WR 3 1992 H
7.2 8 85 85 12 m 365
4.9 17.3 2.4 0.28 5 1.0 6.1 mmol/l 12 6fz6M 3±5 m 90 ± 150 10 WR, dup 4 1989 H

II~index of individuality; Nspec~number of specimens; If~index of ®duciability; S/S~samples/subjects; MM~mathematical model; M~male; f~female; h~hours;
d~days; w~weeks; m~months; y~years; WR~within-run; BR~between-run; dup~duplicate; trip~triplicate; quat~quadruplicate; H~health; P~pathology.
Current databases on biological variation
495
 496 C. RicoÂs et al.

TABLE II.

Desirable speci®cations

Biological variation TE (%)

Analyte CVw CVb I (%) B (%) pv0.05 pv0.01

S 11-Deoxycortisol 21.3 31.5 10.7 6.5 27.1 34.3

S 17-Hydroxyprogesterone 19.6 52.4 9.8 14.0 30.2 36.8
S 5'Nucleotidase 23.2 19.9 11.6 7.6 26.8 34.7
U 5-HIAA concentration, 24 h 20.3 33.2 10.2 9.7 26.5 33.4
S a1-Acid glycoprotein 11.3 24.9 5.7 6.8 16.2 20.0
S a1-Antichymotrypsin 13.5 18.3 6.8 5.7 16.8 21.4
S a1-Antitrypsin 5.9 16.3 3.0 4.3 9.2 11.2
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S a1-Globulins 11.4 22.6 5.7 6.3 15.7 19.6

U a1-Microglobulin concentration, overnight 33.0 58.0 16.5 16.7 43.9 55.1
P a2-Antiplasmin 6.2 ± 3.1 ± ± ±
S a2-Globulins 10.3 12.7 5.2 4.1 12.6 16.1
S a2-Macroglobulin 3.1 18.7 1.7 4.8 7.6 8.7
U a2-Microglobulin output, overnight 29.0 32.0 14.5 10.8 34.7 44.6
S a-Amylase 9.5 29.8 4.8 7.8 15.7 18.9
U a-Amylase concentration, random 94.0 46.0 47.0 26.2 103.7 135.7
S a-Amylase, pancreatic 11.7 29.9 5.9 8.0 17.7 21.7
S a-Carotene 35.8 ± 17.9 ± ± ±
S Acid phosphatase, tartrate-resistant (TR-ACP) 10.8 13.3 5.4 4.3 13.2 16.9
S Acid phosphatase (ACP) 8.9 8.0 4.5 3.0 10.3 13.4
S Acid phosphatase activity, prostatic (PAP) 33.8 ± 16.9 ± ± ±
P Activated partial thromboplastin time 2.7 8.6 1.4 2.3 4.5 5.4
S ADA 11.7 25.5 5.9 7.0 16.7 20.6
For personal use only.

S Alanine aminopeptidase 4.1 ± 2.1 ± ± ±

S Alanine aminotransferase 24.3 41.6 12.2 12.0 32.1 40.4
S Albumin 3.1 4.2 1.6 1.3 3.9 4.9
U Albumin concentration, ®rst morning 36.0 55.0 18.0 16.4 46.1 58.4
S Aldosterone 29.4 40.1 14.7 12.4 36.7 46.7
U Aldosterone concentration, 24 h 32.6 39.0 16.3 12.7 39.6 50.7
S Alkaline phosphatase 6.4 24.8 3.2 6.4 11.7 13.9
S Alkaline phosphatase, bone isoform 6.6 35.6 3.3 9.1 14.5 16.7
S Alkaline phosphatase, placental 19.1 ± 9.6 ± ± ±
U Ammonia output, 24 h 24.7 27.3 12.4 9.2 29.6 38.0
S Androstendione 11.5 51.1 5.8 13.1 22.6 26.5
S Angiotensin converting enzyme 12.5 27.7 6.3 7.6 17.9 22.2
P Antithrombin III 5.2 15.3 2.6 4.0 8.3 10.1
S Apolipoprotein A1 6.5 13.4 3.3 3.7 9.1 11.3
S Apolipoprotein B 6.9 22.8 3.5 6.0 11.6 14.0
S Ascorbic acid' 25.8 22.9 12.9 8.6 29.9 38.7
S Aspartate aminotransferase 11.9 17.9 6.0 5.4 15.2 19.2
S a-Tocopherol 13.8 13.3 6.9 4.8 16.2 20.9
S b2-Microglobulin 5.9 15.5 3.0 4.1 9.0 11.0
B Basophils, count 28.0 54.8 14.0 15.4 38.5 48.0
S b-Carotene 36.0 39.0 18.0 13.3 43.0 55.2
S b-Cryptoxanthin 36.7 ± 18.4 ± ± ±
S b-Globulins 10.1 9.1 5.1 3.4 11.7 15.2
S Bilirubin, conjugated 36.8 43.2 18.4 14.2 44.5 57.1
S Bilirubin, total 25.6 30.5 12.8 10.0 31.1 39.8
S C Peptide 9.3 13.3 4.7 4.1 11.7 14.9
U C Telopeptide type I collagen/creatinine 35.1 ± 17.6 ± ± ±
S C Telopeptide type I procollagen 8.0 28.8 4.0 7.5 14.1 16.8
S C3 complement 5.2 15.6 2.6 4.1 8.4 10.2
S C4 complement 8.9 33.4 4.5 8.6 16.0 19.0
S CA 125 13.6 46.5 6.8 12.1 23.3 28.0
S CA 15.3 5.7 42.9 2.9 10.8 15.5 17.5
S CA 19.9 24.5 93.0 12.3 24.0 44.3 52.6
S CA 549 9.1 33.4 4.6 8.7 16.2 19.3
 Current databases on biological variation 497

TABLE II. (continued)

Desirable speci®cations

Biological variation TE (%)

Analyte CVw CVb I (%) B (%) pv0.05 pv0.01

S Calcium 1.9 2.8 1.0 0.8 2.4 3.1

U Calcium concentration, 24 h 27.5 36.6 13.8 11.4 34.1 43.5
U Calcium output, 24 h 26.2 27.0 13.1 9.4 31.0 39.9
S Carbohydrate de®cient transferrin 7.1 38.7 3.6 9.8 15.7 18.1
S Carcinoembryonic antigen (CEA) 9.3 55.6 4.7 14.1 21.8 24.9
S Ceruloplasmin 5.7 11.1 2.9 3.1 7.8 9.8
S Chloride 1.2 1.5 0.6 0.5 1.5 1.9
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S Cholesterol 6.0 15.2 3.0 4.1 9.0 11.1

S Cholinesterase 7.0 10.4 3.5 3.1 8.9 11.3
S Cholinesterase, immunoreactive 6.4 ± 3.2 ± ± ±
S Cholinesterase, catalytic activity 5.4 10.3 2.7 2.9 7.4 9.2
S CK MB% 6.9 42.8 3.5 10.8 16.5 18.9
S CK MB, activity 19.7 24.3 9.9 7.8 24.1 30.8
S CK MB, mass 18.4 61.2 9.2 16.0 31.2 37.4
P Copper 8.0 19.0 4.0 5.2 11.8 14.5
S Copper 4.9 13.6 2.5 3.6 7.7 9.3
S Cortisol 20.9 45.6 10.5 12.5 29.8 36.9
S C-Propeptide type 1 procollagen 8.2 17.6 4.1 4.9 11.6 14.4
S C-Reactive protein 52.6 84.4 26.3 24.9 68.3 86.1
S Creatine kinase 22.8 40.0 11.4 11.5 60.3 38.1
S Creatinine 4.3 12.9 2.2 3.4 6.9 8.4
Pt Creatinine clearance 13.6 13.5 6.8 4.8 16.0 20.6
For personal use only.

U Creatinine concentration, 24 h 24.0 24.5 12.0 8.6 28.4 36.5

U Creatinine output, 24 h 11.0 23.0 5.5 6.4 15.4 19.2
P Cysteine 5.9 12.3 3.0 3.4 8.3 10.3
S Dehydroepiandrosterone sulfate 3.4 30.0 1.7 7.5 10.4 11.5
U Deoxipyridinoline/creatinine, 24 h 14.7 15.1 7.4 5.3 17.4 22.4
P Dipeptidyl-peptidase IV 8.2 14.5 4.1 4.2 10.9 13.7
P Elastase-PI 13.6 16.4 6.8 5.3 16.5 21.2
B Eosinophils, count 21.0 76.4 10.5 19.8 37.1 44.3
(B)Pl Epinephrine 25.3 ± 12.7 ± ± ±
P Epinephrine 48.3 ± 24.2 ± ± ±
B Erythrocytes, count 3.2 6.1 1.6 1.7 4.4 5.5
U Estradiol 30.4 ± 15.2 ± ± ±
S Estradiol 22.6 24.4 11.3 8.3 27.0 34.6
P Factor V 3.6 ± 1.8 ± ± ±
P Factor VII 6.8 19.4 3.4 5.1 10.7 13.1
P Factor VIII 4.8 19.1 2.4 4.9 8.9 10.5
P Factor X 5.9 ± 3.0 ± ± ±
S Ferritin 14.9 13.5 7.5 5.0 17.3 22.4
P Fibrinogen 10.7 15.8 5.4 4.8 13.6 17.2
S Follicle stimulating hormone 10.1 32.0 5.1 8.4 16.7 20.2
S Free estradiol 22.8 ± 11.4 ± ± ±
U Free estradiol 38.6 ± 19.3 ± ± ±
S Free testosterone 9.3 ± 4.7 ± ± ±
U Free testosterone 51.7 ± 25.9 ± ± ±
S Free thyroxine (FT4) 7.6 12.2 3.8 3.6 9.9 12.4
S Free triiodothyronine (FT3) 7.9 ± 4.0 ± ± ±
S Fructosamine 3.4 5.9 1.7 1.7 4.5 5.7
(B)Ery G6PDH 32.8 31.8 16.4 11.4 38.5 49.6
S c-Globulin 14.6 12.3 7.3 4.8 16.8 21.8
S c-Glutamyltransferase 13.8 41.0 6.9 10.8 22.2 26.9
S Globulins, total 5.5 12.9 2.8 3.5 8.0 9.9
S Glucose 6.5 7.7 3.3 2.5 7.9 10.1
B Glutathione peroxidase 7.2 21.7 3.6 5.7 11.7 14.1
S Glycated albumin 5.2 10.3 2.6 2.9 7.2 8.9
 498 C. RicoÂs et al.

TABLE II. (continued)

Desirable speci®cations

Biological variation TE (%)

Analyte CVw CVb I (%) B (%) pv0.05 pv0.01

S Glycated total protein 0.9 11.6 0.5 2.9 3.7 9.0

(B)Hb Glycohemoglobin 5.6 ± 2.8 ± ± ±
P, S Haptoglobin 20.4 36.4 10.2 10.4 27.3 34.2
S HDL cholesterol 7.1 19.7 3.6 5.2 11.1 13.5
S HDL1 cholesterol 15.5 27.2 2.8 6.9 11.5 13.3
S HDL2 cholesterol 15.7 40.7 7.9 10.9 23.9 29.2
S HDL3 cholesterol 7.0 14.3 3.5 4.0 9.8 12.1
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B Hematocrit 2.8 6.4 1.4 1.7 4.1 5.0

B Hemoglobin 2.8 6.6 1.4 1.8 4.1 5.1
P Homocysteine 7.7 29.9 3.9 7.7 14.1 16.7
U Hydroxiproline/minute, night urine 36.1 38.8 18.1 13.2 43.0 55.3
S Hydroxybutyrate dehydrogenase 8.8 ± 4.4 ± ± ±
S Immunoglobulin A 5.0 36.8 2.5 9.3 13.4 15.1
S Immunoglobulin G 4.5 16.5 2.3 4.3 8.0 9.5
S Immunoglobulin M 5.9 47.3 3.0 11.9 16.8 18.8
S Insulin 21.1 58.3 10.6 15.5 32.9 40.1
(B)Leu Interferon receptor 14.0 20.0 7.0 6.1 17.7 22.4
S Iron 26.5 23.2 13.3 8.8 30.7 39.7
S k-Chains 4.8 15.3 2.4 4.0 8.0 9.6
S l-Chains 4.8 18.0 2.4 4.7 8.6 10.2
B Lactate 27.2 16.7 13.6 8.0 30.4 39.7
S Lactate dehydrogenase (LDH) 6.6 14.7 4.3 4.3 11.4 14.3
For personal use only.

P Lactoferrin 11.8 23.7 5.9 6.6 16.4 20.4

S LD1 6.3 10.2 3.2 3.0 8.2 10.3
S LD2 4.9 4.3 2.5 1.6 5.7 7.3
S LD3 4.8 5.5 2.47 1.8 5.8 7.4
S LD4 9.4 9.0 4.2 3.3 11.0 14.2
S LD5 12.4 13.4 6.2 4.6 14.8 19.0
S LDL cholesterol 8.3 25.7 4.3856 6.8 13.6 16.4
S LDL cholesterol direct 6.5 ± 3.3 ± ± ±
B LDL receptor mRNA 21.5 13.6 10.9 6.4 24.1 31.4
B Leukocytes, count 10.9 19.6 5.3 5.6 14.6 18.3
S Lipase 23.1 33.1 11.6 10.1 29.1 37.0
S Lipoprotein (a) 8.5 85.8 4.3 21.6 28.6 31.5
S Lutein 23.7 ± 11.9 ± ± ±
S Luteinizing hormone 14.5 27.8 7.3 7.8 19.8 24.7
S Lycopenen 43.1 ± 21.6 ± ± ±
B Lymphocytes, count 10.4 27.8 5.2 7.4 16.0 19.5
(B)Ery Magnesium 5.6 11.3 2.8 3.2 7.8 9.7
(B)Leu Magnesium 18.3 16.4 9.2 6.1 21.2 57.5
S Magnesium 3.6 6.4 1.8 1.8 4.8 6.0
U Magnesium concentration, 24 h 45.4 37.4 22.7 14.7 52.2 67.6
U Magnesium output, 24 h 38.3 37.6 19.2 13.4 45.0 58.0
(B)Ery Mean corpuscular hemoglobin (HCM) 1.6 5.2 0.8 1.4 2.7 3.2
(B)Ery Mean corpuscular hemoglobin conc. (MCHC) 1.7 2.8 0.9 0.8 2.2 2.8
(B)Ery Mean corpuscular volume (MCV) 1.3 4.8 0.7 1.2 2.3 2.8
(B)Pl Mean platelet volume (MPV) 4.3 8.1 2.2 2.3 5.8 7.3
B Monocytes, count 17.8 49.8 8.9 13.2 27.9 34.0
S Mucinous carcinoma-associated antigen (MCA) 10.1 39.3 5.1 10.1 18.5 21.9
S Myoglobin 13.9 29.6 7.0 8.2 19.6 24.4
U N Telopeptide type I collagen/creatinine 23.1 ± 11.6 ± ± ±
U N-Acetyl glucosaminidase concentration, overnight 52.5 33.5 26.3 15.6 58.9 76.7
U N-Acetyl glucosaminidase output, overnight 42.4 18.2 21.2 11.5 46.3 60.9
B Neutrophils, count 16.1 32.8 8.1 9.1 22.4 27.9
U Nitrogen, output 13.9 24.2 7.0 7.0 18.4 23.2
(B)Pl Norepinephrine 9.5 ± 4.8 ± ± ±
 Current databases on biological variation 499

TABLE II. (continued)

Desirable speci®cations

Biological variation TE (%)

Analyte CVw CVb I (%) B (%) pv0.05 pv0.01

P Norepinephrine 19.5 ± 9.8 ± ± ±

S N-Propeptide type 1 procollagen 7.4 ± 3.7 ± ± ±
S Osmolality 1.3 1.2 0.7 0.4 1.5 2.0
S Osteocalcin 6.3 23.1 3.2 6.0 11.2 13.3
U Oxalate concentration, 24 h 44.0 18.0 22.0 11.9 48.2 63.1
U Oxalate output, 24 h 42.5 19.9 21.3 11.7 46.8 61.2
B pCO2 4.8 5.3 2.4 1.8 5.7 7.4
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B PH 3.5 2.0 1.8 1.0 3.9 5.1

S Phosphate 8.5 9.4 4.3 3.2 10.2 13.1
U Phosphate concentration, 24 h 26.4 26.5 13.2 9.4 31.1 40.1
U Phosphate output, 24 h 18.0 22.6 9.0 7.2 22.1 28.2
Pt Phosphate tubular reabsorption 2.7 3.3 1.4 1.1 3.3 4.2
S Phospholipids 6.5 11.1 3.3 3.2 8.6 10.8
P Plasminogen 4.7 ± 3.9 ± ± ±
B Platelet distribution wide (PDW) 2.8 ± 1.4 ± ± ±
B Plateletcrit 11.9 ± 6.0 ± ± ±
B Platelets 9.1 21.9 4.6 5.9 13.4 16.5
(B)Leu Potassium 13.6 13.4 6.8 4.8 16.0 20.6
S Potassium 4.8 5.6 2.4 1.8 5.8 7.4
U Potassium concentration, 24 h 27.1 23.2 13.6 8.9 31.3 40.5
U Potassium output, 24 h 24.4 22.2 12.2 8.2 28.4 36.7
S Prealbumin 10.9 19.1 5.5 2.5 14.5 18.2
For personal use only.

S Prolactin (men) 6.9 61.2 3.5 15.4 21.1 23.4

P Prolyl endopeptidase 16.8 13.9 8.4 5.5 19.3 25.0
S Prostatic speci®c antigen (PSA) 14.0 72.4 7.0 18.4 30.0 34.7
P Protein C 5.8 55.2 2.9 13.9 18.7 20.6
U Protein concentration, 24 h 39.6 17.8 19.8 10.9 43.5 57.0
U Protein output, 24 h 35.5 23.7 17.8 10.7 40.0 52.0
P Protein S 5.8 63.4 2.9 15.9 20.7 22.7
S Protein, total 2.7 4.0 1.4 1.2 3.4 4.4
P Prothrombin, time 4.0 6.8 2.0 2.0 5.3 6.6
U Pyridinoline/creatinine, morning spot 8.7 17.6 4.4 4.9 12.1 15.0
B Pyruvate 15.2 13.0 7.6 5.0 17.5 22.7
B Red cell distribution wide (RDW) 3.5 5.7 1.8 1.7 4.6 5.7
S Retinol 14.8 18.3 7.4 5.9 18.1 23.1
S Rheumatoid factor 8.5 24.5 4.3 6.5 13.5 16.4
S SCC 39.4 35.7 19.7 13.3 45.8 59.2
B Selenium 12.0 12.0 6.0 4.2 14.1 18.2
P Selenium 12.0 14.0 6.0 4.6 14.5 18.6
S Sex hormone binding globulin (SHBG) 12.1 42.7 6.1 11.1 21.1 25.2
(B)Ery Sodium 1.8 12.4 0.9 3.1 4.6 5.2
(B)Leu Sodium 51.0 36.4 25.5 15.7 57.7 75.1
S Sodium 0.7 1.0 0.4 0.3 0.9 1.1
U Sodium concentration, 24 h 24.0 26.8 12.0 9.0 28.8 37.0
U Sodium output, 24 h 28.7 16.7 14.4 8.3 32.0 41.7
S Superoxide dismutase 17.1 10.5 8.6 5.0 19.1 24.9
(B)Ery Superoxide dismutase 12.3 4.9 6.2 3.3 13.5 17.6
S T3-uptake 4.5 4.5 2.3 1.6 5.3 6.8
S Testosterone 8.8 21.3 4.4 5.8 13.0 16.0
Sa Testosterone 17.3 28.8 8.7 7.2 21.4 27.3
U Testosterone 25.0 ± 12.5 ± ± ±
S Thyroglobulin 13.0 25.0 6.5 7.0 17.8 22.2
S Thyroid stimulating hormone (TSH) 19.7 27.2 9.9 8.4 24.6 31.3
S Thyroxin binding globulin (TBG) 6.0 6.0 3.0 2.1 7.1 9.1
S Thyroxine (T4) 6.0 12.1 3.0 3.4 8.3 10.4
S Tissue polypeptide speci®c antigen (TPS) 36.1 108.0 18.1 28.5 58.3 70.5
 500 C. RicoÂs et al.

TABLE II. (continued)

Desirable speci®cations

Biological variation TE (%)

Analyte CVw CVb I (%) B (%) pv0.05 pv0.01

S Tissue polypeptide antigen (TPA) 28.7 40.4 14.4 12.4 36.1 45.8
U Total catecholamines, concentration, 24 h 24.0 32.0 12.0 10.0 29.8 38.0
S Transferrin 3.0 4.3 1.5 1.3 3.8 4.8
S Triglyceride 21.0 37.2 10.5 10.7 28.0 35.1
S Triiodothyronine (T3) 8.7 14.4 4.4 4.2 11.4 14.3
S Urate 8.6 17.2 4.3 4.8 11.9 14.8
U Urate concentration, 24 h 24.7 22.1 12.4 8.3 28.7 37.1
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U Urate output, 24 h 18.5 14.4 9.3 5.9 21.1 27.4

S Urea 12.3 18.3 6.2 5.5 15.7 19.8
U Urea concentration, 24 h 22.7 25.9 11.4 8.6 27.3 35.1
U Urea output, 24 h 17.4 25.4 8.7 7.7 22.1 28.0
U Vanilmandelic acid concentration, 24 h 22.2 47.0 11.1 13.0 31.3 38.9
S VLDL cholesterol 27.6 ± 13.8 ± ± ±
P Von Willebrand factor 0.001 28.3 0.0005 7.1 7.1 7.1
S Water 3.3 0.1 1.6 0.8 3.3 4.4
S Zeaxanthine 34.7 ± 17.4 ± ± ±
P Zinc 11.0 14.0 5.5 4.5 13.5 17.3
S Zinc 9.3 9.4 4.7 3.3 11.0 14.1

S~serum; U~urine; P~plasma; Bl~blood; Pl~platelets; Ery~erythrocytes; Hb~hemoglobin; Leu~leuko-

cytes; Pt~patient; Sa~saliva; I~precision; B~bias; TE~total error.
For personal use only.

information, those relevant only locally and
those with little objective discussion.
Several quantities (particularly hormones)
have been studied in very few articles and the
results found are highly discrepant. Profes-
sionals in laboratory medicine should be
strongly encouraged to study the quantities
for which results are discrepant, the 90
described in only one paper and the numerous
quantities that have not been the subject of
study.
ACKNOWLEDGEMENTS
We express our thanks to Paco Campos and
Carlos GonzaÂlez-Oller for their time and
dedication. We also thank Callum Fraser, Per
Hyltof Petersen and Jean Claude Libeer for
their valuable help in the planning of this work.
REFERENCES
2 Fraser CG. The application of theoretical goals
based on biological variation data in pro®ciency
testing. Arch Pathol Lab Med 1988; 112: 404 ± 15.
3 Fraser CG. Biological variation in clinical chem-
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Pathol Lab Med 1992; 116: 916 ± 23.
4 SebastiaÂn-Gambaro MA, LiroÂn HernaÂndez PJ,
fuentes-Arderiu X. Intra- and inter-individual
biological variability data bank. Eur J Clin Chem
Clin Biochem (1997); 35: 845 ± 52 (also available at
www.westgard.co).
5 Fraser CG, Hyltoft Petersen P, RicoÂs C, Haeckel R.
Proposed quality speci®cations for the imprecision
and inaccuracy of analytical systems for clinical
chemistry. Eur J Clin Chem Clin Biochem 1992; 30:
311 ± 7.
6 RicoÂs C, Alvarez V, JimeÂnez CV, HernaÂndez A,
Minchinela J, Perich C, SimoÂn M. Transferability
of results produced in the clinical laboratory. Quim
Clin (1996); 15: 442 ± 4; 1997; 16: 218.
7 Fraser CG, Harris EK. Generation and application
of data on biological variation in clinical chemistry.
Crit Rev Lab Sci 1989; 27: 409 ± 37.
8 Fraser CG, Browning MCK. The ``Index of
®duciability'' proposed for use in evaluation and
comparison of methods. Clin Chem 1988; 34:
1356 ± 7.

1 Ross JW. Evaluation of precision. In: Werner M,

editor. Handbook of clinical chemistry, Vol. 1. Received: 25 April 1999
Boca Raton: CRC Press, 1982: 391 ± 42. Accepted: 27 September 1999