Scand J Clin Lab Invest 1999; 59: 491 500

Current databases on biological variation: pros,

cons and progress
C. RIC O S , V. A L V A R EZ, F. C A V A , J . V . G ARCI A -L A R I O, A . H E R N A NDEZ,
C. V. JIME N E Z , J . M I N C H I N E L A , C. PE R I C H & M . S I M O N
Analytical Quality Commission from the Spanish Society of Clinical Chemistry and Molecular
Pathology (SEQC), Spain

Ricos C, Alvarez V, Cava F, Garca-Lario JV, Hernandez A, Jimenez CV,

Minchinela J, Perich C, Simon M. Current databases on biological variation:
pros, cons and progress. Scand J Clin Lab Invest 1999; 59: 491500.
A database with reliable information to derive denitive analytical quality
specications 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,
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 betweensubject coefcients of variation and the subsequent desirable quality specications for precision, bias and total error for all the quantities accepted are
presented. Sex-related stratication of results was justied for only four
quantities and, in these cases, quality specications 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 specications 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 specications; bias; biological variation; database;
precision
C. Ricos, 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
Models based on biological variation provide
well-accepted bases for deriving quality goals

in clinical laboratories for general purposes,

such as screening, case-nding, diagnosis and
monitoring. The components of biological
variation, expressed in percentages, are the
491

492

C. Ricos 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 presented: Ross [1], Fraser [2, 3] and SebastianGambaro et al. [4]. In 1992, the European
Group for the Evaluation of Reagents and
Analytical Systems in Laboratory Medicine
(EGELAB) published quality specications for
imprecision and bias (at that time termed
``inaccuracy'') for 34 quantities [5]. The Spanish
Society of Clinical Biochemistry and Molecular
Pathology (SEQC) has recommended quality
specications for imprecision, bias, bias in
alternative sites and total error for 50 serum
and urine quantities [6]. The quality specications 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 denitive quality specications
for precision, bias and total error for a large
number of clinical laboratory tests. This was
achieved by comparing and correlating descriptive 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 classied 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 withinsubject to between-subject variation), refer-

ence change value (RCV, difference between

two consecutive measurements of one analyte in a person and representing a signicant
change in health status), number of specimens 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, standard deviation and units of measurement
obtained for each population studied in each
article, total number of subjects included and
stratied 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 coefcient 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 inuence the calculation of the components, 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 classied 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 components 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.

Current databases on biological variation

For each analyte, all articles having If w2
and/or classied 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).
When such relationships were found, these
articles were separated from the general evaluation and their CVw and CVb were calculated
individually.
When there were no trends requiring separation of articles into groups, the medians of the
within- and between-subject CV from all the
articles referring to the specic analyte were
calculated to determine the quality specications.
Desirable quality specications for precision
(I), bias (B) and total error (TE) were calculated
using the following formulae:
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 scientic 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,

493

therefore, the estimations of components from

these articles were considered unsuitable for
deriving quality specications.
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 specications.
Table II shows the desirable quality specications for precision, bias and total error for all of
the quantities accepted from the bibliography
studied.

D ISCU SSION
This work focused on establishing denitive
analytical quality specications 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 quantities.
The following ndings are highlighted.
. The CVw and CVb from articles included in
groups 4 and 3 (according to the mathematical model used) are very similar, demonstrating the robustness of the formula
proposed by Fraser & Harris [7], which was
used by the majority of authors studied.
. Sex-related stratication of results was justied for only four quantities and, in these
cases, quality specications 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 specications 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 specications derived from incomplete sources of

3.4
3.5
2.5
1.5
3.6
2.8
4.4
2.4
3.9
6.0
4.8
3.7
4.3
5.1
4.8
5.3
5.2
5.2
4.7
4.4
7.1
4.2
4.8
6.8
7.7
5.1
4.2
4.2
8.3
3.6
7.8
7.8
6.7
7.2
7.5
7.0
4.2
4.8
4.4

CVw

9.0
17.4
15.1

15.2

19.5
11.4

10.2

19.0

CVb

3.1
1.7
1.7
2.0
1.7
2.3
1.0
2.9
2.9
2.9
4.6
1.8
3.0
6.3
1.0
2.7
2.5
2.5
1.68
1.68
1.70
1.1
1.68
1.68

2.2
1.3
1.3
4.3
2.3

3.1
5.7
2.9
2.9
2.9
1.8
1.6

CVa

II

0.47
0.48
0.24

0.29

0.25
0.46

0.36

0.32

TABLE I. S-cholesterol.

4
7
3
2
4
2
4
1
4
6
4
5
4
4
4
6
5
5
5
4
9
3
5
9
11
8
4
5
17
3
11
11
8
9
10
8
3
4
4

Nspec

1.2
0.7
0.7
0.9
0.8
0.6
0.5
1.2
0.8
0.8
1.8
0.9
1.4
1.5
0.6
0.7
0.6
0.7
0.5
0.4
0.5
0.5
0.7
0.8

1.1
0.4
0.5
2.3
1.1

1.8
3.2
2.3
3.8
1.6
1.3
0.7

IF

mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
mmol/l

4.5
5.6
5.6
6.0
4.5
4.6

mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
g/l
g/l

mmol/l
mmol/l
mmol/l
mmol/l

mg/dl
mg/dl
mmol/l

mmol/l
mmol/l
mmol/l
mmol/l
mmol/l
mmol/l

mmol/l

Units

4.4

2.0
1.9

5.8

4.5
5.0
5.0
232.0

4.8
4.6

5.2
5.4
4.4
4.6
5.21
5.8

Mean

n
11
11
28
14
11
62
25
11
10
10
51
5
20
25
14
11
10
10
35
10
20
11
28
14
11
83
83
40
5
10
13
17
11
16
11
14
41
10
14
14
11
10 (M)
10 (F)
35 (M)
10
20
11
28 (M)
14 (F)
11 (F)
83
83
40
5 (F)
10
13
17 (M)
11 (F)
16 (M)
11 (F)
14 (M)
41
10 (M)
14 (F)

11
11
28 (M)
14 (F)
11 (F)
62
25
11
10
10
51
5 (F)
20

n (sex)
0.5 h
8h
1d
1d
1d
1d
1d
1d
5d
5d
5d
5d
1 w
1 w
1.4 w
2 w
4 w
4 w
4 w
4 w
4 w
4 w
1m
1m
1m
1m
2m
36 w
5 w
5 w
5 w
60 w
60 w
8 w
8 w
8 w
8 w
8 w
8 w

Time
0.0208
0.33
1
1
1
1
1
1
5
5
5
5
7
7
9.8
14
28
28
28
28
28
28
30
30
30
30
31
32
35
35
35
42
42
56
56
56
56
56
56

Days

8
8

5
5
20
5
5
8
8
8

6
5
7
7
4
4
4
4
8
8
8
3
3

4
4
4
4
6
5
3
5
3
5
2

S/S

WR, dup
WR
WR
WR, dup
WR, dup
WR, dup
WR, dup
WR, dup
WR, dup
WR, dup
WR, dup

WR, dup
WR, dup
WR, dup
BR
WR, dup
BR, dup
BR
BR
BR
BR
WR
WR

BR, trip
BR
BR
WR, dup
BR
WR, dup

BR
BR
BR
WR

WR

CVa types

1
1
1
3
3
4
2
3
2
4
4
3
2
3
3
3
1
3
3
4
1
1
1
3
3

4
2
Various
1
1
3
3
3
1
3
3

MM

1992
1993
1994
1979
1979
1987
1987
1988
1987
1987
1987

1982
1982
1982
1985
1990
1990
1980
1989
1990
1992
1988
1989
1976
1974
1987
1987
1996
1978
1990
1990
1982
1982
1982
1996
1997

1974

Year

H
H
H
H
H
P
P
P
H
H
H

H
H
H
H
H
H
H
H
H
H
H
H
H
H
P
P
P
H
H
H
H
H
H
H
H

State

494
C. Ricos et al.

0.9
0.9

2.4

17.3

1.8
2.9
2.9
2.9
1.7

12.6
14.6
15.4
9.9

19.5
19.4

13.0
11.0
17.6

13.6
18.3

13.9

17.9

1.70
0.7
3.7
2.0
4.0
4.0
4.9
1.8
2.0
2.0
3.9
3.9
4.6
5.7
1.9
4.0
1.8
1.8
2.5
1.0

0.28

0.52
0.51
0.45
0.71

0.42
0.48

0.32
0.53
0.45

0.48
0.32

0.30

0.44

4
5
5
11
12
10
7
6
5
5
9
8
15
8
6
13
7
9
12
14
8
7
7
10
8
8
9
8
8
8
5

1.0

0.3
0.3

0.6
0.9
0.8
0.9
0.5

0.7
0.3
1.8
0.5
1.1
1.2
2.3
0.7
0.8
0.8
1.2
1.3
1.1
2.8
0.7
1.0
0.6
0.5
0.6
0.2

6.1

5.3
5.1

5.2

194.0

5.1

6.3
4.7
5.4
5.4

204.1
191.0
6.2
6.2
205.0
205.0

5.2

4.5
1.9

mmol/l

mmol/l
mmol/l

mg/dl
mmol/l
mmol/l
mmol/l
mmol/l

mmol/l
mmol/l
mmol/l
mmol/l
mg/l
mmol/l

mg/dl
mg/dl
mmol/l
mmol/l
mg/dl
mg/dl

mmol/l

mmol/l
g/l

10
20
16
1105
1061
611
9
11
128
128
34
34
10
11
27
5
148
126
44
26
85
11
28
14
11
20
14 600
23
19
85
12

10 (M)
20
16
1105
1061 (M)
611 (F)
9
11
128
128
34 (M)
34 (F)
10
11
27
5 (F)
148 (M)
126 (F)
44 (F)
26
85 (M)
11
28 (M)
14 (F)
11 (F)
20
14 600
23 (M)
19 (F)
85
6fz6M

8w
8w
8w
8.5 w
2m
2m
10 w
10 w
10 w
10 w
16 w
16 w
19 w
15 w
20 w
5m
6m
6m
6m
6m
1 y
12 m
12 m
12 m
12 m
1 y
12 m
12 m
12 m
12 m
35 m

56
56
56
59.5
60
60
70
70
70
77
112
112
133
135
140
150
180
180
180
180
365
365
365
365
365
365
365
365
365
365
90 150
10

13
13

10
5
6
6
3
8
4
19
12
12
12
12

10
10
3
3
11
11

8
4

WR, dup

WR
WR

BR, quat
BR
BR
BR
BR

WR, dup
WR, dup
WR
WR
WR
WR, dup

BR, dup
BR, quat
BR, dup
BR, dup
BR, dup
BR, dup

BR

WR, dup

4
4
3
3
3
3
1
3
1
1
1
3
1
3
3

3
3
3
3
3
3

3
3

1989

1989
1992
1985
1985
1990
1997
1987
1976
1982
1982
1982
1989
1990
1992
1992

1971
1976
1992
1992
1970
1970

1978

1988
1994

H
H
H
H
H
H
P
H
H
H
H
H
H
H
H

P
H
H

H
H

H
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.

4.8
5.3
4.2
7.9
7.5
6.6
4.2
5.4
5.0
5.0
6.5
5.9
8.7
4.1
5.8
7.9
6.0
7.2
8.2
9.3
7.2
6.2
6.1
7.3
6.2
6.6
7.4
7.0
7.0
7.2
4.9

Current databases on biological variation

495

496

C. Ricos et al.

TABLE II.
Desirable specications
Biological variation
Analyte
S
S
S
U
S
S
S
S
U
P
S
S
U
S
U
S
S
S
S
S
P
S
S
S
S
U
S
U
S
S
S
U
S
S
P
S
S
S
S
S
S
B
S
S
S
S
S
S
U
S
S
S
S
S
S
S

11-Deoxycortisol
17-Hydroxyprogesterone
5'Nucleotidase
5-HIAA concentration, 24 h
a1-Acid glycoprotein
a1-Antichymotrypsin
a1-Antitrypsin
a1-Globulins
a1-Microglobulin concentration, overnight
a2-Antiplasmin
a2-Globulins
a2-Macroglobulin
a2-Microglobulin output, overnight
a-Amylase
a-Amylase concentration, random
a-Amylase, pancreatic
a-Carotene
Acid phosphatase, tartrate-resistant (TR-ACP)
Acid phosphatase (ACP)
Acid phosphatase activity, prostatic (PAP)
Activated partial thromboplastin time
ADA
Alanine aminopeptidase
Alanine aminotransferase
Albumin
Albumin concentration, rst morning
Aldosterone
Aldosterone concentration, 24 h
Alkaline phosphatase
Alkaline phosphatase, bone isoform
Alkaline phosphatase, placental
Ammonia output, 24 h
Androstendione
Angiotensin converting enzyme
Antithrombin III
Apolipoprotein A1
Apolipoprotein B
Ascorbic acid'
Aspartate aminotransferase
a-Tocopherol
b2-Microglobulin
Basophils, count
b-Carotene
b-Cryptoxanthin
b-Globulins
Bilirubin, conjugated
Bilirubin, total
C Peptide
C Telopeptide type I collagen/creatinine
C Telopeptide type I procollagen
C3 complement
C4 complement
CA 125
CA 15.3
CA 19.9
CA 549

CVw
21.3
19.6
23.2
20.3
11.3
13.5
5.9
11.4
33.0
6.2
10.3
3.1
29.0
9.5
94.0
11.7
35.8
10.8
8.9
33.8
2.7
11.7
4.1
24.3
3.1
36.0
29.4
32.6
6.4
6.6
19.1
24.7
11.5
12.5
5.2
6.5
6.9
25.8
11.9
13.8
5.9
28.0
36.0
36.7
10.1
36.8
25.6
9.3
35.1
8.0
5.2
8.9
13.6
5.7
24.5
9.1

CVb
31.5
52.4
19.9
33.2
24.9
18.3
16.3
22.6
58.0

12.7
18.7
32.0
29.8
46.0
29.9

13.3
8.0

8.6
25.5

41.6
4.2
55.0
40.1
39.0
24.8
35.6

27.3
51.1
27.7
15.3
13.4
22.8
22.9
17.9
13.3
15.5
54.8
39.0

9.1
43.2
30.5
13.3

28.8
15.6
33.4
46.5
42.9
93.0
33.4

TE (%)
I (%) B (%) pv0.05 pv0.01
10.7
9.8
11.6
10.2
5.7
6.8
3.0
5.7
16.5
3.1
5.2
1.7
14.5
4.8
47.0
5.9
17.9
5.4
4.5
16.9
1.4
5.9
2.1
12.2
1.6
18.0
14.7
16.3
3.2
3.3
9.6
12.4
5.8
6.3
2.6
3.3
3.5
12.9
6.0
6.9
3.0
14.0
18.0
18.4
5.1
18.4
12.8
4.7
17.6
4.0
2.6
4.5
6.8
2.9
12.3
4.6

6.5
14.0
7.6
9.7
6.8
5.7
4.3
6.3
16.7

4.1
4.8
10.8
7.8
26.2
8.0

4.3
3.0

2.3
7.0

12.0
1.3
16.4
12.4
12.7
6.4
9.1

9.2
13.1
7.6
4.0
3.7
6.0
8.6
5.4
4.8
4.1
15.4
13.3

3.4
14.2
10.0
4.1

7.5
4.1
8.6
12.1
10.8
24.0
8.7

27.1
30.2
26.8
26.5
16.2
16.8
9.2
15.7
43.9

12.6
7.6
34.7
15.7
103.7
17.7

13.2
10.3

4.5
16.7

32.1
3.9
46.1
36.7
39.6
11.7
14.5

29.6
22.6
17.9
8.3
9.1
11.6
29.9
15.2
16.2
9.0
38.5
43.0

11.7
44.5
31.1
11.7

14.1
8.4
16.0
23.3
15.5
44.3
16.2

34.3
36.8
34.7
33.4
20.0
21.4
11.2
19.6
55.1

16.1
8.7
44.6
18.9
135.7
21.7

16.9
13.4

5.4
20.6

40.4
4.9
58.4
46.7
50.7
13.9
16.7

38.0
26.5
22.2
10.1
11.3
14.0
38.7
19.2
20.9
11.0
48.0
55.2

15.2
57.1
39.8
14.9

16.8
10.2
19.0
28.0
17.5
52.6
19.3

Current databases on biological variation

TABLE II.

497

(continued)
Desirable specications
Biological variation
Analyte

S
U
U
S
S
S
S
S
S
S
S
S
S
S
P
S
S
S
S
S
S
Pt
U
U
P
S
U
P
P
B
(B)Pl
P
B
U
S
P
P
P
P
S
P
S
S
U
S
U
S
S
S
(B)Ery
S
S
S
S
B
S

Calcium
Calcium concentration, 24 h
Calcium output, 24 h
Carbohydrate decient transferrin
Carcinoembryonic antigen (CEA)
Ceruloplasmin
Chloride
Cholesterol
Cholinesterase
Cholinesterase, immunoreactive
Cholinesterase, catalytic activity
CK MB%
CK MB, activity
CK MB, mass
Copper
Copper
Cortisol
C-Propeptide type 1 procollagen
C-Reactive protein
Creatine kinase
Creatinine
Creatinine clearance
Creatinine concentration, 24 h
Creatinine output, 24 h
Cysteine
Dehydroepiandrosterone sulfate
Deoxipyridinoline/creatinine, 24 h
Dipeptidyl-peptidase IV
Elastase-PI
Eosinophils, count
Epinephrine
Epinephrine
Erythrocytes, count
Estradiol
Estradiol
Factor V
Factor VII
Factor VIII
Factor X
Ferritin
Fibrinogen
Follicle stimulating hormone
Free estradiol
Free estradiol
Free testosterone
Free testosterone
Free thyroxine (FT4)
Free triiodothyronine (FT3)
Fructosamine
G6PDH
c-Globulin
c-Glutamyltransferase
Globulins, total
Glucose
Glutathione peroxidase
Glycated albumin

CVw
1.9
27.5
26.2
7.1
9.3
5.7
1.2
6.0
7.0
6.4
5.4
6.9
19.7
18.4
8.0
4.9
20.9
8.2
52.6
22.8
4.3
13.6
24.0
11.0
5.9
3.4
14.7
8.2
13.6
21.0
25.3
48.3
3.2
30.4
22.6
3.6
6.8
4.8
5.9
14.9
10.7
10.1
22.8
38.6
9.3
51.7
7.6
7.9
3.4
32.8
14.6
13.8
5.5
6.5
7.2
5.2

CVb
2.8
36.6
27.0
38.7
55.6
11.1
1.5
15.2
10.4

10.3
42.8
24.3
61.2
19.0
13.6
45.6
17.6
84.4
40.0
12.9
13.5
24.5
23.0
12.3
30.0
15.1
14.5
16.4
76.4

6.1

24.4

19.4
19.1

13.5
15.8
32.0

12.2

5.9
31.8
12.3
41.0
12.9
7.7
21.7
10.3

TE (%)
I (%) B (%) pv0.05 pv0.01
1.0
13.8
13.1
3.6
4.7
2.9
0.6
3.0
3.5
3.2
2.7
3.5
9.9
9.2
4.0
2.5
10.5
4.1
26.3
11.4
2.2
6.8
12.0
5.5
3.0
1.7
7.4
4.1
6.8
10.5
12.7
24.2
1.6
15.2
11.3
1.8
3.4
2.4
3.0
7.5
5.4
5.1
11.4
19.3
4.7
25.9
3.8
4.0
1.7
16.4
7.3
6.9
2.8
3.3
3.6
2.6

0.8
11.4
9.4
9.8
14.1
3.1
0.5
4.1
3.1

2.9
10.8
7.8
16.0
5.2
3.6
12.5
4.9
24.9
11.5
3.4
4.8
8.6
6.4
3.4
7.5
5.3
4.2
5.3
19.8

1.7

8.3

5.1
4.9

5.0
4.8
8.4

3.6

1.7
11.4
4.8
10.8
3.5
2.5
5.7
2.9

2.4
34.1
31.0
15.7
21.8
7.8
1.5
9.0
8.9

7.4
16.5
24.1
31.2
11.8
7.7
29.8
11.6
68.3
60.3
6.9
16.0
28.4
15.4
8.3
10.4
17.4
10.9
16.5
37.1

4.4

27.0

10.7
8.9

17.3
13.6
16.7

9.9

4.5
38.5
16.8
22.2
8.0
7.9
11.7
7.2

3.1
43.5
39.9
18.1
24.9
9.8
1.9
11.1
11.3

9.2
18.9
30.8
37.4
14.5
9.3
36.9
14.4
86.1
38.1
8.4
20.6
36.5
19.2
10.3
11.5
22.4
13.7
21.2
44.3

5.5

34.6

13.1
10.5

22.4
17.2
20.2

12.4

5.7
49.6
21.8
26.9
9.9
10.1
14.1
8.9

498

C. Ricos et al.

TABLE II. (continued)

Desirable specications
Biological variation
Analyte
S
(B)Hb
P, S
S
S
S
S
B
B
P
U
S
S
S
S
S
(B)Leu
S
S
S
B
S
P
S
S
S
S
S
S
S
B
B
S
S
S
S
S
B
(B)Ery
(B)Leu
S
U
U
(B)Ery
(B)Ery
(B)Ery
(B)Pl
B
S
S
U
U
U
B
U
(B)Pl

Glycated total protein

Glycohemoglobin
Haptoglobin
HDL cholesterol
HDL1 cholesterol
HDL2 cholesterol
HDL3 cholesterol
Hematocrit
Hemoglobin
Homocysteine
Hydroxiproline/minute, night urine
Hydroxybutyrate dehydrogenase
Immunoglobulin A
Immunoglobulin G
Immunoglobulin M
Insulin
Interferon receptor
Iron
k-Chains
l-Chains
Lactate
Lactate dehydrogenase (LDH)
Lactoferrin
LD1
LD2
LD3
LD4
LD5
LDL cholesterol
LDL cholesterol direct
LDL receptor mRNA
Leukocytes, count
Lipase
Lipoprotein (a)
Lutein
Luteinizing hormone
Lycopenen
Lymphocytes, count
Magnesium
Magnesium
Magnesium
Magnesium concentration, 24 h
Magnesium output, 24 h
Mean corpuscular hemoglobin (HCM)
Mean corpuscular hemoglobin conc. (MCHC)
Mean corpuscular volume (MCV)
Mean platelet volume (MPV)
Monocytes, count
Mucinous carcinoma-associated antigen (MCA)
Myoglobin
N Telopeptide type I collagen/creatinine
N-Acetyl glucosaminidase concentration, overnight
N-Acetyl glucosaminidase output, overnight
Neutrophils, count
Nitrogen, output
Norepinephrine

CVw
0.9
5.6
20.4
7.1
15.5
15.7
7.0
2.8
2.8
7.7
36.1
8.8
5.0
4.5
5.9
21.1
14.0
26.5
4.8
4.8
27.2
6.6
11.8
6.3
4.9
4.8
9.4
12.4
8.3
6.5
21.5
10.9
23.1
8.5
23.7
14.5
43.1
10.4
5.6
18.3
3.6
45.4
38.3
1.6
1.7
1.3
4.3
17.8
10.1
13.9
23.1
52.5
42.4
16.1
13.9
9.5

CVb
11.6

36.4
19.7
27.2
40.7
14.3
6.4
6.6
29.9
38.8

36.8
16.5
47.3
58.3
20.0
23.2
15.3
18.0
16.7
14.7
23.7
10.2
4.3
5.5
9.0
13.4
25.7

13.6
19.6
33.1
85.8

27.8

27.8
11.3
16.4
6.4
37.4
37.6
5.2
2.8
4.8
8.1
49.8
39.3
29.6

33.5
18.2
32.8
24.2

TE (%)
I (%) B (%) pv0.05 pv0.01
0.5
2.8
10.2
3.6
2.8
7.9
3.5
1.4
1.4
3.9
18.1
4.4
2.5
2.3
3.0
10.6
7.0
13.3
2.4
2.4
13.6
4.3
5.9
3.2
2.5
2.47
4.2
6.2
4.3856
3.3
10.9
5.3
11.6
4.3
11.9
7.3
21.6
5.2
2.8
9.2
1.8
22.7
19.2
0.8
0.9
0.7
2.2
8.9
5.1
7.0
11.6
26.3
21.2
8.1
7.0
4.8

2.9

10.4
5.2
6.9
10.9
4.0
1.7
1.8
7.7
13.2

9.3
4.3
11.9
15.5
6.1
8.8
4.0
4.7
8.0
4.3
6.6
3.0
1.6
1.8
3.3
4.6
6.8

6.4
5.6
10.1
21.6

7.8

7.4
3.2
6.1
1.8
14.7
13.4
1.4
0.8
1.2
2.3
13.2
10.1
8.2

15.6
11.5
9.1
7.0

3.7

27.3
11.1
11.5
23.9
9.8
4.1
4.1
14.1
43.0

13.4
8.0
16.8
32.9
17.7
30.7
8.0
8.6
30.4
11.4
16.4
8.2
5.7
5.8
11.0
14.8
13.6

24.1
14.6
29.1
28.6

19.8

16.0
7.8
21.2
4.8
52.2
45.0
2.7
2.2
2.3
5.8
27.9
18.5
19.6

58.9
46.3
22.4
18.4

9.0

34.2
13.5
13.3
29.2
12.1
5.0
5.1
16.7
55.3

15.1
9.5
18.8
40.1
22.4
39.7
9.6
10.2
39.7
14.3
20.4
10.3
7.3
7.4
14.2
19.0
16.4

31.4
18.3
37.0
31.5

24.7

19.5
9.7
57.5
6.0
67.6
58.0
3.2
2.8
2.8
7.3
34.0
21.9
24.4

76.7
60.9
27.9
23.2

Current databases on biological variation

TABLE II.

499

(continued)
Desirable specications
Biological variation
Analyte

P
S
S
S
U
U
B
B
S
U
U
Pt
S
P
B
B
B
(B)Leu
S
U
U
S
S
P
S
P
U
U
P
S
P
U
B
B
S
S
S
B
P
S
(B)Ery
(B)Leu
S
U
U
S
(B)Ery
S
S
Sa
U
S
S
S
S
S

Norepinephrine
N-Propeptide type 1 procollagen
Osmolality
Osteocalcin
Oxalate concentration, 24 h
Oxalate output, 24 h
pCO2
PH
Phosphate
Phosphate concentration, 24 h
Phosphate output, 24 h
Phosphate tubular reabsorption
Phospholipids
Plasminogen
Platelet distribution wide (PDW)
Plateletcrit
Platelets
Potassium
Potassium
Potassium concentration, 24 h
Potassium output, 24 h
Prealbumin
Prolactin (men)
Prolyl endopeptidase
Prostatic specic antigen (PSA)
Protein C
Protein concentration, 24 h
Protein output, 24 h
Protein S
Protein, total
Prothrombin, time
Pyridinoline/creatinine, morning spot
Pyruvate
Red cell distribution wide (RDW)
Retinol
Rheumatoid factor
SCC
Selenium
Selenium
Sex hormone binding globulin (SHBG)
Sodium
Sodium
Sodium
Sodium concentration, 24 h
Sodium output, 24 h
Superoxide dismutase
Superoxide dismutase
T3-uptake
Testosterone
Testosterone
Testosterone
Thyroglobulin
Thyroid stimulating hormone (TSH)
Thyroxin binding globulin (TBG)
Thyroxine (T4)
Tissue polypeptide specic antigen (TPS)

CVw
19.5
7.4
1.3
6.3
44.0
42.5
4.8
3.5
8.5
26.4
18.0
2.7
6.5
4.7
2.8
11.9
9.1
13.6
4.8
27.1
24.4
10.9
6.9
16.8
14.0
5.8
39.6
35.5
5.8
2.7
4.0
8.7
15.2
3.5
14.8
8.5
39.4
12.0
12.0
12.1
1.8
51.0
0.7
24.0
28.7
17.1
12.3
4.5
8.8
17.3
25.0
13.0
19.7
6.0
6.0
36.1

CVb

1.2
23.1
18.0
19.9
5.3
2.0
9.4
26.5
22.6
3.3
11.1

21.9
13.4
5.6
23.2
22.2
19.1
61.2
13.9
72.4
55.2
17.8
23.7
63.4
4.0
6.8
17.6
13.0
5.7
18.3
24.5
35.7
12.0
14.0
42.7
12.4
36.4
1.0
26.8
16.7
10.5
4.9
4.5
21.3
28.8

25.0
27.2
6.0
12.1
108.0

TE (%)
I (%) B (%) pv0.05 pv0.01
9.8
3.7
0.7
3.2
22.0
21.3
2.4
1.8
4.3
13.2
9.0
1.4
3.3
3.9
1.4
6.0
4.6
6.8
2.4
13.6
12.2
5.5
3.5
8.4
7.0
2.9
19.8
17.8
2.9
1.4
2.0
4.4
7.6
1.8
7.4
4.3
19.7
6.0
6.0
6.1
0.9
25.5
0.4
12.0
14.4
8.6
6.2
2.3
4.4
8.7
12.5
6.5
9.9
3.0
3.0
18.1

0.4
6.0
11.9
11.7
1.8
1.0
3.2
9.4
7.2
1.1
3.2

5.9
4.8
1.8
8.9
8.2
2.5
15.4
5.5
18.4
13.9
10.9
10.7
15.9
1.2
2.0
4.9
5.0
1.7
5.9
6.5
13.3
4.2
4.6
11.1
3.1
15.7
0.3
9.0
8.3
5.0
3.3
1.6
5.8
7.2

7.0
8.4
2.1
3.4
28.5

1.5
11.2
48.2
46.8
5.7
3.9
10.2
31.1
22.1
3.3
8.6

13.4
16.0
5.8
31.3
28.4
14.5
21.1
19.3
30.0
18.7
43.5
40.0
20.7
3.4
5.3
12.1
17.5
4.6
18.1
13.5
45.8
14.1
14.5
21.1
4.6
57.7
0.9
28.8
32.0
19.1
13.5
5.3
13.0
21.4

17.8
24.6
7.1
8.3
58.3

2.0
13.3
63.1
61.2
7.4
5.1
13.1
40.1
28.2
4.2
10.8

16.5
20.6
7.4
40.5
36.7
18.2
23.4
25.0
34.7
20.6
57.0
52.0
22.7
4.4
6.6
15.0
22.7
5.7
23.1
16.4
59.2
18.2
18.6
25.2
5.2
75.1
1.1
37.0
41.7
24.9
17.6
6.8
16.0
27.3

22.2
31.3
9.1
10.4
70.5

500

C. Ricos et al.

TABLE II. (continued)

Desirable specications
Biological variation
Analyte
S
U
S
S
S
S
U
U
S
U
U
U
S
P
S
S
P
S

Tissue polypeptide antigen (TPA)

Total catecholamines, concentration, 24 h
Transferrin
Triglyceride
Triiodothyronine (T3)
Urate
Urate concentration, 24 h
Urate output, 24 h
Urea
Urea concentration, 24 h
Urea output, 24 h
Vanilmandelic acid concentration, 24 h
VLDL cholesterol
Von Willebrand factor
Water
Zeaxanthine
Zinc
Zinc

CVw
28.7
24.0
3.0
21.0
8.7
8.6
24.7
18.5
12.3
22.7
17.4
22.2
27.6
0.001
3.3
34.7
11.0
9.3

CVb
40.4
32.0
4.3
37.2
14.4
17.2
22.1
14.4
18.3
25.9
25.4
47.0

28.3
0.1

14.0
9.4

TE (%)
I (%) B (%) pv0.05 pv0.01
14.4
12.0
1.5
10.5
4.4
4.3
12.4
9.3
6.2
11.4
8.7
11.1
13.8
0.0005
1.6
17.4
5.5
4.7

12.4
10.0
1.3
10.7
4.2
4.8
8.3
5.9
5.5
8.6
7.7
13.0

7.1
0.8

4.5
3.3

36.1
29.8
3.8
28.0
11.4
11.9
28.7
21.1
15.7
27.3
22.1
31.3

7.1
3.3

13.5
11.0

45.8
38.0
4.8
35.1
14.3
14.8
37.1
27.4
19.8
35.1
28.0
38.9

7.1
4.4

17.3
14.1

S~serum; U~urine; P~plasma; Bl~blood; Pl~platelets; Ery~erythrocytes; Hb~hemoglobin; Leu~leukocytes; Pt~patient; Sa~saliva; I~precision; B~bias; TE~total error.

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. Professionals 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 Gonzalez-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.

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Received: 25 April 1999

Accepted: 27 September 1999