biological variation

Current databases on biological variation: pros,cons and progress

C. RICOÂ S, V. ALVAREZ, F. CAVA, J. V. GARCIÂ A-LARIO, A. HERNAÂ NDEZ,

C. V. JIMEÂ NEZ, J. MINCHINELA, C. PERICH & M. SIMOÂ N

Analytical Quality Commission from the Spanish Society of Clinical Chemistry and Molecular

Pathology (SEQC), Spain

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,

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

INTRODUCTION

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

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

491

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

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 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.

492 C. RicoÂs et al.

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).

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:

Iv0.5CVw

Bv0.25 (CVw2zCVb

2)c

TEv1.65IzB (av0.05)

TEv2.33IzB (av0.01).

RESULTS

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,

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.

DISCUSSION

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

Current databases on biological variation 493

TA

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1992

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1989

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1987

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1996

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1978

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1990

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1990

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0.3

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51

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m150

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1992

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.87

0.6

5.4

mm

ol/

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148

(M)

6m

180

6W

R3

1985

H7

.21

.89

0.5

5.4

mm

ol/

l126

126

(F)

6m

180

6W

R3

1985

H8

.21

9.5

2.5

0.4

21

20

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g/l

44

44

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6m

180

3W

R3

1990

H9

.31

9.4

1.0

0.4

81

40

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mm

ol/

l26

26

6m

180

8W

R,

du

p3

1997

H7

.28

85

85

(M)

1y

365

41

1987

P6

.21

.87

0.6

194.0

mg/d

l11

11

12

m365

19

BR

,q

uat

31976

H6

.12

.97

0.9

mm

ol/

l28

28

(M)

12

m365

12

BR

11982

H7

.32

.91

00

.8m

mo

l/l

14

14

(F)

12

m365

12

BR

11982

H6

.22

.98

0.9

mm

ol/

l11

11

(F)

12

m365

12

BR

11982

H6

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2.6

1.7

0.5

28

0.5

5.2

mm

ol/

l20

20

1y

365

12

BR

31989

H7

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4.6

0.5

19

14

600

14

600

12

m365

11990

H7

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5.4

0.9

0.4

58

0.3

5.3

mm

ol/

l23

23

(M)

12

m365

13

WR

31992

H7

.09

.90

.90

.71

80

.35.1

mm

ol/

l19

19

(F)

12

m365

13

WR

31992

H7

.28

85

85

12

m365

4.9

17

.32

.40

.28

51

.06.1

mm

ol/

l12

6fz

6M

3±

5m

90

±150

10

WR

,d

up

41989

H

II~index

ofindividuality;Nspec

~number

ofspecim

ens;If

~index

of®duciability;S/S

~samples/subjects;MM

~mathem

aticalmodel;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.


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 34.3S 17-Hydroxyprogesterone 19.6 52.4 9.8 14.0 30.2 36.8S 5'Nucleotidase 23.2 19.9 11.6 7.6 26.8 34.7U 5-HIAA concentration, 24 h 20.3 33.2 10.2 9.7 26.5 33.4S a1-Acid glycoprotein 11.3 24.9 5.7 6.8 16.2 20.0S a1-Antichymotrypsin 13.5 18.3 6.8 5.7 16.8 21.4S a1-Antitrypsin 5.9 16.3 3.0 4.3 9.2 11.2S a1-Globulins 11.4 22.6 5.7 6.3 15.7 19.6U a1-Microglobulin concentration, overnight 33.0 58.0 16.5 16.7 43.9 55.1P a2-Antiplasmin 6.2 ± 3.1 ± ± ±S a2-Globulins 10.3 12.7 5.2 4.1 12.6 16.1S a2-Macroglobulin 3.1 18.7 1.7 4.8 7.6 8.7U a2-Microglobulin output, overnight 29.0 32.0 14.5 10.8 34.7 44.6S a-Amylase 9.5 29.8 4.8 7.8 15.7 18.9U a-Amylase concentration, random 94.0 46.0 47.0 26.2 103.7 135.7S a-Amylase, pancreatic 11.7 29.9 5.9 8.0 17.7 21.7S a-Carotene 35.8 ± 17.9 ± ± ±S Acid phosphatase, tartrate-resistant (TR-ACP) 10.8 13.3 5.4 4.3 13.2 16.9S Acid phosphatase (ACP) 8.9 8.0 4.5 3.0 10.3 13.4S Acid phosphatase activity, prostatic (PAP) 33.8 ± 16.9 ± ± ±P Activated partial thromboplastin time 2.7 8.6 1.4 2.3 4.5 5.4S ADA 11.7 25.5 5.9 7.0 16.7 20.6S Alanine aminopeptidase 4.1 ± 2.1 ± ± ±S Alanine aminotransferase 24.3 41.6 12.2 12.0 32.1 40.4S Albumin 3.1 4.2 1.6 1.3 3.9 4.9U Albumin concentration, ®rst morning 36.0 55.0 18.0 16.4 46.1 58.4S Aldosterone 29.4 40.1 14.7 12.4 36.7 46.7U Aldosterone concentration, 24 h 32.6 39.0 16.3 12.7 39.6 50.7S Alkaline phosphatase 6.4 24.8 3.2 6.4 11.7 13.9S Alkaline phosphatase, bone isoform 6.6 35.6 3.3 9.1 14.5 16.7S Alkaline phosphatase, placental 19.1 ± 9.6 ± ± ±U Ammonia output, 24 h 24.7 27.3 12.4 9.2 29.6 38.0S Androstendione 11.5 51.1 5.8 13.1 22.6 26.5S Angiotensin converting enzyme 12.5 27.7 6.3 7.6 17.9 22.2P Antithrombin III 5.2 15.3 2.6 4.0 8.3 10.1S Apolipoprotein A1 6.5 13.4 3.3 3.7 9.1 11.3S Apolipoprotein B 6.9 22.8 3.5 6.0 11.6 14.0S Ascorbic acid' 25.8 22.9 12.9 8.6 29.9 38.7S Aspartate aminotransferase 11.9 17.9 6.0 5.4 15.2 19.2S a-Tocopherol 13.8 13.3 6.9 4.8 16.2 20.9S b2-Microglobulin 5.9 15.5 3.0 4.1 9.0 11.0B Basophils, count 28.0 54.8 14.0 15.4 38.5 48.0S b-Carotene 36.0 39.0 18.0 13.3 43.0 55.2S b-Cryptoxanthin 36.7 ± 18.4 ± ± ±S b-Globulins 10.1 9.1 5.1 3.4 11.7 15.2S Bilirubin, conjugated 36.8 43.2 18.4 14.2 44.5 57.1S Bilirubin, total 25.6 30.5 12.8 10.0 31.1 39.8S C Peptide 9.3 13.3 4.7 4.1 11.7 14.9U 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 16.8S C3 complement 5.2 15.6 2.6 4.1 8.4 10.2S C4 complement 8.9 33.4 4.5 8.6 16.0 19.0S CA 125 13.6 46.5 6.8 12.1 23.3 28.0S CA 15.3 5.7 42.9 2.9 10.8 15.5 17.5S CA 19.9 24.5 93.0 12.3 24.0 44.3 52.6S CA 549 9.1 33.4 4.6 8.7 16.2 19.3


S Calcium 1.9 2.8 1.0 0.8 2.4 3.1U Calcium concentration, 24 h 27.5 36.6 13.8 11.4 34.1 43.5U Calcium output, 24 h 26.2 27.0 13.1 9.4 31.0 39.9S Carbohydrate de®cient transferrin 7.1 38.7 3.6 9.8 15.7 18.1S Carcinoembryonic antigen (CEA) 9.3 55.6 4.7 14.1 21.8 24.9S Ceruloplasmin 5.7 11.1 2.9 3.1 7.8 9.8S Chloride 1.2 1.5 0.6 0.5 1.5 1.9S Cholesterol 6.0 15.2 3.0 4.1 9.0 11.1S Cholinesterase 7.0 10.4 3.5 3.1 8.9 11.3S Cholinesterase, immunoreactive 6.4 ± 3.2 ± ± ±S Cholinesterase, catalytic activity 5.4 10.3 2.7 2.9 7.4 9.2S CK MB% 6.9 42.8 3.5 10.8 16.5 18.9S CK MB, activity 19.7 24.3 9.9 7.8 24.1 30.8S CK MB, mass 18.4 61.2 9.2 16.0 31.2 37.4P Copper 8.0 19.0 4.0 5.2 11.8 14.5S Copper 4.9 13.6 2.5 3.6 7.7 9.3S Cortisol 20.9 45.6 10.5 12.5 29.8 36.9S C-Propeptide type 1 procollagen 8.2 17.6 4.1 4.9 11.6 14.4S C-Reactive protein 52.6 84.4 26.3 24.9 68.3 86.1S Creatine kinase 22.8 40.0 11.4 11.5 60.3 38.1S Creatinine 4.3 12.9 2.2 3.4 6.9 8.4Pt Creatinine clearance 13.6 13.5 6.8 4.8 16.0 20.6U Creatinine concentration, 24 h 24.0 24.5 12.0 8.6 28.4 36.5U Creatinine output, 24 h 11.0 23.0 5.5 6.4 15.4 19.2P Cysteine 5.9 12.3 3.0 3.4 8.3 10.3S Dehydroepiandrosterone sulfate 3.4 30.0 1.7 7.5 10.4 11.5U Deoxipyridinoline/creatinine, 24 h 14.7 15.1 7.4 5.3 17.4 22.4P Dipeptidyl-peptidase IV 8.2 14.5 4.1 4.2 10.9 13.7P Elastase-PI 13.6 16.4 6.8 5.3 16.5 21.2B 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 5.5U Estradiol 30.4 ± 15.2 ± ± ±S Estradiol 22.6 24.4 11.3 8.3 27.0 34.6P Factor V 3.6 ± 1.8 ± ± ±P Factor VII 6.8 19.4 3.4 5.1 10.7 13.1P Factor VIII 4.8 19.1 2.4 4.9 8.9 10.5P Factor X 5.9 ± 3.0 ± ± ±S Ferritin 14.9 13.5 7.5 5.0 17.3 22.4P Fibrinogen 10.7 15.8 5.4 4.8 13.6 17.2S Follicle stimulating hormone 10.1 32.0 5.1 8.4 16.7 20.2S 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 12.4S 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 49.6S c-Globulin 14.6 12.3 7.3 4.8 16.8 21.8S c-Glutamyltransferase 13.8 41.0 6.9 10.8 22.2 26.9S Globulins, total 5.5 12.9 2.8 3.5 8.0 9.9S Glucose 6.5 7.7 3.3 2.5 7.9 10.1B Glutathione peroxidase 7.2 21.7 3.6 5.7 11.7 14.1S Glycated albumin 5.2 10.3 2.6 2.9 7.2 8.9

TABLE II. (continued)









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 34.2S HDL cholesterol 7.1 19.7 3.6 5.2 11.1 13.5S HDL1 cholesterol 15.5 27.2 2.8 6.9 11.5 13.3S HDL2 cholesterol 15.7 40.7 7.9 10.9 23.9 29.2S HDL3 cholesterol 7.0 14.3 3.5 4.0 9.8 12.1B Hematocrit 2.8 6.4 1.4 1.7 4.1 5.0B Hemoglobin 2.8 6.6 1.4 1.8 4.1 5.1P Homocysteine 7.7 29.9 3.9 7.7 14.1 16.7U Hydroxiproline/minute, night urine 36.1 38.8 18.1 13.2 43.0 55.3S Hydroxybutyrate dehydrogenase 8.8 ± 4.4 ± ± ±S Immunoglobulin A 5.0 36.8 2.5 9.3 13.4 15.1S Immunoglobulin G 4.5 16.5 2.3 4.3 8.0 9.5S Immunoglobulin M 5.9 47.3 3.0 11.9 16.8 18.8S 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 22.4S Iron 26.5 23.2 13.3 8.8 30.7 39.7S k-Chains 4.8 15.3 2.4 4.0 8.0 9.6S l-Chains 4.8 18.0 2.4 4.7 8.6 10.2B Lactate 27.2 16.7 13.6 8.0 30.4 39.7S Lactate dehydrogenase (LDH) 6.6 14.7 4.3 4.3 11.4 14.3P Lactoferrin 11.8 23.7 5.9 6.6 16.4 20.4S LD1 6.3 10.2 3.2 3.0 8.2 10.3S LD2 4.9 4.3 2.5 1.6 5.7 7.3S LD3 4.8 5.5 2.47 1.8 5.8 7.4S LD4 9.4 9.0 4.2 3.3 11.0 14.2S LD5 12.4 13.4 6.2 4.6 14.8 19.0S LDL cholesterol 8.3 25.7 4.3856 6.8 13.6 16.4S LDL cholesterol direct 6.5 ± 3.3 ± ± ±B LDL receptor mRNA 21.5 13.6 10.9 6.4 24.1 31.4B Leukocytes, count 10.9 19.6 5.3 5.6 14.6 18.3S Lipase 23.1 33.1 11.6 10.1 29.1 37.0S Lipoprotein (a) 8.5 85.8 4.3 21.6 28.6 31.5S Lutein 23.7 ± 11.9 ± ± ±S Luteinizing hormone 14.5 27.8 7.3 7.8 19.8 24.7S 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 57.5S Magnesium 3.6 6.4 1.8 1.8 4.8 6.0U Magnesium concentration, 24 h 45.4 37.4 22.7 14.7 52.2 67.6U 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 7.3B Monocytes, count 17.8 49.8 8.9 13.2 27.9 34.0S Mucinous carcinoma-associated antigen (MCA) 10.1 39.3 5.1 10.1 18.5 21.9S Myoglobin 13.9 29.6 7.0 8.2 19.6 24.4U 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 76.7U N-Acetyl glucosaminidase output, overnight 42.4 18.2 21.2 11.5 46.3 60.9B Neutrophils, count 16.1 32.8 8.1 9.1 22.4 27.9U Nitrogen, output 13.9 24.2 7.0 7.0 18.4 23.2(B)Pl Norepinephrine 9.5 ± 4.8 ± ± ±






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 2.0S Osteocalcin 6.3 23.1 3.2 6.0 11.2 13.3U Oxalate concentration, 24 h 44.0 18.0 22.0 11.9 48.2 63.1U Oxalate output, 24 h 42.5 19.9 21.3 11.7 46.8 61.2B pCO2 4.8 5.3 2.4 1.8 5.7 7.4B PH 3.5 2.0 1.8 1.0 3.9 5.1S Phosphate 8.5 9.4 4.3 3.2 10.2 13.1U Phosphate concentration, 24 h 26.4 26.5 13.2 9.4 31.1 40.1U Phosphate output, 24 h 18.0 22.6 9.0 7.2 22.1 28.2Pt Phosphate tubular reabsorption 2.7 3.3 1.4 1.1 3.3 4.2S Phospholipids 6.5 11.1 3.3 3.2 8.6 10.8P 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 20.6S Potassium 4.8 5.6 2.4 1.8 5.8 7.4U Potassium concentration, 24 h 27.1 23.2 13.6 8.9 31.3 40.5U Potassium output, 24 h 24.4 22.2 12.2 8.2 28.4 36.7S Prealbumin 10.9 19.1 5.5 2.5 14.5 18.2S Prolactin (men) 6.9 61.2 3.5 15.4 21.1 23.4P Prolyl endopeptidase 16.8 13.9 8.4 5.5 19.3 25.0S Prostatic speci®c antigen (PSA) 14.0 72.4 7.0 18.4 30.0 34.7P Protein C 5.8 55.2 2.9 13.9 18.7 20.6U Protein concentration, 24 h 39.6 17.8 19.8 10.9 43.5 57.0U Protein output, 24 h 35.5 23.7 17.8 10.7 40.0 52.0P Protein S 5.8 63.4 2.9 15.9 20.7 22.7S Protein, total 2.7 4.0 1.4 1.2 3.4 4.4P Prothrombin, time 4.0 6.8 2.0 2.0 5.3 6.6U Pyridinoline/creatinine, morning spot 8.7 17.6 4.4 4.9 12.1 15.0B Pyruvate 15.2 13.0 7.6 5.0 17.5 22.7B Red cell distribution wide (RDW) 3.5 5.7 1.8 1.7 4.6 5.7S Retinol 14.8 18.3 7.4 5.9 18.1 23.1S Rheumatoid factor 8.5 24.5 4.3 6.5 13.5 16.4S SCC 39.4 35.7 19.7 13.3 45.8 59.2B Selenium 12.0 12.0 6.0 4.2 14.1 18.2P Selenium 12.0 14.0 6.0 4.6 14.5 18.6S 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 75.1S Sodium 0.7 1.0 0.4 0.3 0.9 1.1U Sodium concentration, 24 h 24.0 26.8 12.0 9.0 28.8 37.0U Sodium output, 24 h 28.7 16.7 14.4 8.3 32.0 41.7S 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 17.6S T3-uptake 4.5 4.5 2.3 1.6 5.3 6.8S Testosterone 8.8 21.3 4.4 5.8 13.0 16.0Sa Testosterone 17.3 28.8 8.7 7.2 21.4 27.3U Testosterone 25.0 ± 12.5 ± ± ±S Thyroglobulin 13.0 25.0 6.5 7.0 17.8 22.2S Thyroid stimulating hormone (TSH) 19.7 27.2 9.9 8.4 24.6 31.3S Thyroxin binding globulin (TBG) 6.0 6.0 3.0 2.1 7.1 9.1S Thyroxine (T4) 6.0 12.1 3.0 3.4 8.3 10.4S Tissue polypeptide speci®c antigen (TPS) 36.1 108.0 18.1 28.5 58.3 70.5


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 GonzaÂ lez-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

1 Ross JW. Evaluation of precision. In: Werner M,editor. Handbook of clinical chemistry, Vol. 1.Boca Raton: CRC Press, 1982: 391 ± 42.

2 Fraser CG. The application of theoretical goalsbased on biological variation data in pro®ciencytesting. Arch Pathol Lab Med 1988; 112: 404 ± 15.

3 Fraser CG. Biological variation in clinical chem-istry: an update. Collated data, 1988 ± 1991. ArchPathol Lab Med 1992; 116: 916 ± 23.

4 SebastiaÂn-Gambaro MA, LiroÂn HernaÂndez PJ,fuentes-Arderiu X. Intra- and inter-individualbiological variability data bank. Eur J Clin ChemClin Biochem (1997); 35: 845 ± 52 (also available atwww.westgard.co).

5 Fraser CG, Hyltoft Petersen P, RicoÂs C, Haeckel R.Proposed quality speci®cations for the imprecisionand inaccuracy of analytical systems for clinicalchemistry. 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. Transferabilityof results produced in the clinical laboratory. QuimClin (1996); 15: 442 ± 4; 1997; 16: 218.

7 Fraser CG, Harris EK. Generation and applicationof 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 andcomparison of methods. Clin Chem 1988; 34:1356 ± 7.

Received: 25 April 1999Accepted: 27 September 1999





S Tissue polypeptide antigen (TPA) 28.7 40.4 14.4 12.4 36.1 45.8U Total catecholamines, concentration, 24 h 24.0 32.0 12.0 10.0 29.8 38.0S Transferrin 3.0 4.3 1.5 1.3 3.8 4.8S Triglyceride 21.0 37.2 10.5 10.7 28.0 35.1S Triiodothyronine (T3) 8.7 14.4 4.4 4.2 11.4 14.3S Urate 8.6 17.2 4.3 4.8 11.9 14.8U Urate concentration, 24 h 24.7 22.1 12.4 8.3 28.7 37.1U Urate output, 24 h 18.5 14.4 9.3 5.9 21.1 27.4S Urea 12.3 18.3 6.2 5.5 15.7 19.8U Urea concentration, 24 h 22.7 25.9 11.4 8.6 27.3 35.1U Urea output, 24 h 17.4 25.4 8.7 7.7 22.1 28.0U Vanilmandelic acid concentration, 24 h 22.2 47.0 11.1 13.0 31.3 38.9S VLDL cholesterol 27.6 ± 13.8 ± ± ±P Von Willebrand factor 0.001 28.3 0.0005 7.1 7.1 7.1S Water 3.3 0.1 1.6 0.8 3.3 4.4S Zeaxanthine 34.7 ± 17.4 ± ± ±P Zinc 11.0 14.0 5.5 4.5 13.5 17.3S 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.


biological variation

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