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The Athlete Biological Passport

Article in Clinical Chemistry · May 2011

DOI: 10.1373/clinchem.2011.162271 · Source: PubMed

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Clinical Chemistry 57:7
969–976 (2011) Reviews

The Athlete Biological Passport

Pierre-Edouard Sottas,1* Neil Robinson,1 Olivier Rabin,2 and Martial Saugy1

BACKGROUND: In elite sports, the growing availability of core values of natural performance, protection of
doping substances identical to those naturally pro- health, and the spirit of the sport (1 ). Accordingly, a
duced by the human body seriously limits the ability of substance or method is considered for prohibition if it
drug-testing regimes to ensure fairness and protection violates at least 2 of these 3 values. The primary tool

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of health. used by sports authorities to ensure a doping-free sport
has been the detection of prohibited substances in the
CONTENT: The Athlete Biological Passport (ABP), the biological fluids of athletes, specifically urine and
new paradigm in testing based on the personalized blood. This drug-testing paradigm was introduced in
monitoring of biomarkers of doping, offers the enor- the 1960s (Table 1) and has since been remarkably suc-
mous advantage of being independent of this endless cessful in the detection of substances that are not nat-
pharmaceutical race. Doping triggers physiological urally produced by the body, such as stimulants, nar-
changes that provide physiological enhancements. In cotics, ␤2-agonists, and diuretics. This success is largely
the same way that disease-related biomarkers are in- attributed to the use of chromatography coupled to
valuable tools that assist physicians in the diagnosis of mass spectrometry techniques that have revolutionized
pathology, specifically selected biomarkers can be used the detection of a large number of compounds (2 ).
to detect doping. As a result of advances in biotechnology, the phar-
maceutical industry continues to market new drugs at a
SUMMARY: The ABP is a new testing paradigm with im-
remarkable pace. A substantial number of these new
mense potential value in the current climate of rapid
substances are recombinant proteins or peptides that
advancement in biomarker discovery. In addition to its
are strikingly similar in structure, and in some in-
original aim of providing proof of a doping offense, the
stances absolutely identical, to those naturally pro-
ABP can also serve as a platform for a Rule of Sport,
duced by the human body. The identification of these
with the presentation before competition of the ABP to
substances in biological fluids can be difficult or virtu-
objectively demonstrate that the athlete will participate
ally impossible in some cases. In modern sports, doped
in a healthy physiological condition that is unaltered by
athletes are in a constant race with antidoping re-
performance-enhancing drugs. Finally, the decision-
searchers, who must employ great ingenuity to develop
support system used today for the biological monitor-
toxicology tests capable of distinguishing exogenous
ing of world top-level athletes can also be advanta-
substances from their endogenous counterparts. In ad-
geously transferred to other areas of clinical practice to
dition, detection is further complicated by the medical
reach the goal of personalized medicine.
supervision and increased sophistication of doping
© 2011 American Association for Clinical Chemistry
protocols. Contemporary protocols are shifting to-
wards long cycles of small microdoses taken repeatedly
that are difficult to detect by using conventional drug
The promotion of ethical values and the protection of tests. Worse, designer drugs are currently being pro-
health in and throughout sports are the primary objec- duced by black-market laboratories to get around ex-
tives of the sport movement. In that context, the abuse isting drug tests. Consequently, the drug-testing para-
of substance doping represents the most serious threat digm established in the 1960s cannot prevent elite
to the integrity of modern sports. The World Anti- athletes from doping with impunity when using many
Doping Code, the reference document that provides the potent doping substances such as designer recombi-
framework for harmonized antidoping rules within nant erythropoietin (rEPO)3 and designer testoster-
sports organizations, has been written to preserve the one. For these reasons, alternative strategies that are
independent of this endless pharmaceutical race must
be developed to maintain fairness in elite sports.
1
Swiss Laboratory for Anti-Doping Analyses, Chemin des Croisettes, 1066 Lau-
sanne, Switzerland; 2 World Anti-Doping Agency, Montreal, Canada
* Address correspondence to this author at: Swiss Laboratory for Doping Anal-
yses, Croisettes Epalinges, 1066 Lausanne Switzerland. Fax ⫹41-21-3147333; 3
Nonstandard abbreviations: rEPO, recombinant erythropoietin; ESA,
e-mail [email protected]. erythropoiesis-stimulating agents; HGB, hemoglobin concentration; HCT, he-
Received January 23, 2011; accepted April 20, 2011. matocrit; T/E, testosterone/epitestosterone; ABP, Athlete Biological Passport;
Previously published online at DOI: 10.1373/clinchem.2011.162271 WADA, World Anti-Doping Agency.

969
Reviews

most common medical tests in a full blood count pro-

Table 1. History of anti-doping. file, has been used as a biomarker of blood doping. In
the mid-1990s, some sports federations introduced up-
Year Event
per limits on HGB and hematocrit (HCT) levels, and
1928 The IAAF becomes the first federation to ban athletes with values above these limits were temporar-
doping ily suspended from competition in an attempt to limit
1966 The IAAF, the Union Cycliste Internationale (UCI), the abuse of rEPO. Interestingly, such doping biomark-
and the Fédération Internationale de Football ers are independent from the marketing of novel dop-
Association (FIFA) introduce urine drug tests in
their respective championships ing substances, and although the pharmaceutical in-
1967 The International Olympic Committee (IOC)
dustry continues to market new drugs every year, the

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institutes its Medical Commission and sets up biology of the human body is relatively stable for gen-
the first list of prohibited substances eral physiological functions. The evolution of the hu-
1968 Drug tests introduced at the Olympic Games man body takes at least several generations, and owing
1970s Marked increase in the number of doping-related to this biological stability, a biomarker of doping such
disqualifications after the introduction by the as hemoglobin measurement will remain sensitive to
IOC of anabolic steroids to its list of prohibited any past, present, or future ESA abuse.
substances
As a result, there is an ongoing paradigm shift in
1980s Introduction of out-of-competition testing testing, from the direct identification of banned sub-
1986 blood transfusion banned by IOC stances in the biological fluids of athletes to the detec-
1990 rEPO included in the IOC’s list of prohibited tion of abnormalities in biomarkers that potentially in-
substances dicate that doping has occurred. Although it is difficult
1990s Introduction of blood tests to predict which of the new ESAs will be available dur-
1999 WADA is established ing the 2016 Olympic Games in Rio de Janeiro and
2004 The World Anti-Doping Code is adopted beyond, the biological characteristics of the athletes
worldwide participating in these games will not differ from the
2005 United Nations Educational, Scientific and biological characteristics of athletes that are competing
Cultural Organization (UNESCO) adopts the today. Consequently, all of the doping biomarkers that
International Convention against Doping in
Sport
have already been developed will remain applicable in
the upcoming Olympic Games and for several decades
2008 The UCI is the first federation to introduce the
Athlete Biological Passport into the future, whereas a toxicology test must be es-
tablished for almost every newly marketed drug. For
example, today’s biomarkers of blood doping are al-
ready sensitive to gene doping with the human EPO
A Paradigm Shift in Testing gene.

The development of erythropoiesis-stimulating agents Biomarkers of Doping

(ESA) for the treatment of anemia has been a highly
active field over the past 2 decades, wherein 6 different Athletes who abuse doping substances do so to trigger
rEPOs have been licensed worldwide and more than 90 physiological changes that provide physiological en-
biosimilar rEPOs or copies have become available in hancements. Therefore, in the same way that disease-
countries with low regulatory controls of pharmaceu- related biomarkers are invaluable tools that assist phy-
tical products (3 ). This frenzied rhythm is expected to sicians in the diagnosis of pathology, doping can be
continue because new generations of ESAs are expected detected from specifically selected biomarkers. Gener-
in the near future, such as the synthetic peptide-based ally, the effect of the drug remains detectable in the
EPO receptor agonist Hematide™; the conjugated body much longer than the substance itself, which can
EPO-mimetic peptide Sestide™; hypoxia-inducible be quickly excreted and therefore go undetected by
transcription factor stabilizers, such as FG-2216™; and toxicology testing.
modified cells that carry the human EPO gene or the The use of biomarkers of doping is not new. For
EPO protein, such as EpoDure™. In parallel with in- example, the testosterone/epitestosterone concen-
creasing numbers of prescribed ESAs, some designer tration ratio (T/E) was introduced by several sports
rEPOs have been created by black market laboratories organizations in the 1970s to deter the administra-
to get around existing drug tests. tion of anabolic steroids. Because epitestosterone is
All ESAs aim to improve oxygen transport by the only a minor product of testosterone metabolism
metalloprotein hemoglobin. Consequently, measure- and does not increase after exogenous testosterone
ment of hemoglobin concentration (HGB), one of the administration, the net effect of the latter is an in-

970 Clinical Chemistry 57:7 (2011)

The Athlete Biological Passport
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crease in T/E (4 ). In 1983, a T/E in excess of 6.0 was athlete’s historical values and the values obtained in
considered indicative of steroid doping by the Inter- a recent test indicate that either doping has taken
national Olympic Committee. The introduction of place or that the athlete has a potential medical con-
this rule was mitigated, however, by the discovery a dition that requires closer examination (20 ). The
few years later that some individuals may have nat- concept of the ABP has been discussed and then fur-
urally increased T/E (5 ), a phenomenon that has re- ther elaborated for antidoping application by the
cently been attributed to the discovery of genetic World Anti Doping Agency (WADA) beginning in
polymorphisms that are associated with the metab- 2002. Since the 2006 Torino Winter Olympic Games,
olism of anabolic steroids (6 ). Currently, in addition several international sports federations have agreed
to the T/E, a urinary steroid profile that includes that the WADA should harmonize the development

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multiple testosterone metabolites and precursors is and validation of the ABP program. As a result, in
used to detect steroid doping (Fig. 3), in addition to 2009, the WADA published the Athlete Biological
doping with other anabolic agents, such as designer Passport Operating Guidelines (23 ), which can be
steroids, gonadotropins, estrogen antagonists, aro- used as a reference for any antidoping organizations
matase inhibitors, androgen precursors, and selec- that are interested in developing a concordant bio-
tive androgen receptor modulators (7, 8 ). logical monitoring program.
The development and validation of blood-doping Three distinct modules can be distinguished in the
biomarkers have also greatly evolved since the intro- ABP: the hematological, steroidal, and endocrinologi-
duction of hematological variables by some interna- cal modules. The hematological module of the ABP
tional sports federations in the mid-1990s. With the aims to detect any form of blood doping (22 ). As part
advent of automated blood analyzers, blood variables of a full blood count, 8 hematological variables are con-
can be quantitatively measured to yield a complete he- sidered today in this module. In 2008, the Union Cy-
mogram, either in an accredited laboratory or directly cliste Internationale was the first sports organization to
at the location of the competition, in less than a minute implement the hematological module of the ABP to
after blood collection (9 ). Several approaches have deter blood doping in elite cycling (Fig. 1), and subse-
contributed in recent years to make the use of biomark- quently, several riders have been prosecuted and sanc-
ers of altered erythropoiesis an efficient approach to tioned on the sole basis of their abnormal hemato-
deterring any form of blood doping in sports: (a) the logical profiles. Currently, hematological tracing is
introduction of multiparametric blood-doping mark- performed by several antidoping organizations for sev-
ers (10, 11 ); (b) the inclusion of heterogeneous factors, eral thousand athletes worldwide. The steroidal mod-
such as sex and age, as recommended by the WHO in ule of the ABP, which aims to detect direct and indirect
the diagnosis of anemia (12 ), as well as other factors forms of doping with anabolic agents (7 ), is presently
specific to sports (13, 14 ); (c) the add-on of potentially being finalized for implementation in the near future.
confounding factors, such as the athlete’s exposure to The endocrinological module of the ABP aims to detect
altitude (15 ); (d) the record of the athlete’s own previ- doping with growth factors, such as growth hormone
ous measurements (16 –18 ), with the underlying con- and insulin growth factor-1. Despite abundant scien-
cept being the use the athlete as his or her own refer- tific publications on growth hormone– dependent
ence (19 –21 ); (e) the adoption of standardized markers (24 ), the implementation of the endocrino-
protocols for sample collection and analysis, in addi- logical module in the ABP in the network of WADA-
tion to the extensive use of external QC systems to con- accredited laboratories requires further validation to
trol analytical uncertainty (22 ); and (f) the develop- fulfill forensic standards.
ment and validation of probabilistic inference Biological fluids, such as blood and urine, contain
techniques to evaluate the value of doping evidence a treasure trove of potential doping markers that can be
(17, 18 ). discovered by today’s omics techniques, such as pro-
teomics and metabolomics. The usefulness of this gold
The Athlete Biological Passport mine for diagnostic purposes has been recognized
(25 ), and the same is true for doping biomarkers. By
All of the knowledge that has been acquired in recent definition, any deviation in a biomarker from what is
decades concerning doping biomarkers has been expected in a healthy physiological condition accord-
formalized in the ABP program. The term passport ing to well-defined protocols can be attributable only
was first proposed in the early 2000s when the pres- to doping or a medical condition. Interestingly, these 2
ervation and tracking of a longitudinal record of he- possible causes are the exact targets of any antidoping
matological variable measurements were planned to program; hence, the criteria that are used to introduce
be used as a means to define an individual’s hema- new biomarkers into the ABP are the same as those that
tological profile (19 ). Large disparities between an are used to define a banned substance, more specifi-

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Fig. 1. Hematological passport of an elite rider tested on 9 occasions for 4 markers of blood doping: HGB, the
stimulation index OFF-score (OFFS), the Abnormal Blood Profile Score (ABPS), and the percentage of reticulocytes
(RET%).
Blue lines represent actual test results. Red lines indicate limits at which the test result is considered abnormal. Initial limits (e.g.,
124 –172 g/L for HGB) are based on population epidemiology and are adapted in the course of individual data acquisition to produce
individual final limits (121–150 g/L for HGB). Color bars indicate sequence (seq) abnormality [Sottas et al. (22)]; prob, probability. The
numerous abnormalities suggest that it is very unlikely that such a blood profile would not be obtained under normal physiological
conditions. The rider was subsequently convicted of doping with the variant of rEPO known as CERA (continuous erythropoiesis
receptor activator). How to calculate OFF-score and ABPS can be found in Gore et al. (10) and Sottas et al. (11), respectively.

cally, the criteria of performance and health. In addi- medical controls or treatments. This short period of
tion, an eligibility rule becomes a logical consequence debarment could also be used by a panel of experts to
of this assumption, wherein athletes present their pass- determine the cause of the abnormality and may lead to
ports at the beginning of a competition and individuals sanctioning the athlete for a longer period if doping is
are allowed to participate only if their passport indi- the cause.
cates that they are in a healthy and unaltered physio- Although the ABP had the initial exclusive intent
logical condition. Therefore, in addition to proving a of biological monitoring, today, the ABP contains
doping offense under the World Anti-Doping Code, more than a simple series of individual biomarker val-
the ABP can be a platform for a Rule of Sport enforced ues. Heterogeneous factors, such as age, sex, and geno-
by the sport authorities to prevent athletes from ma- type; confounding factors, such as exposure to higher
nipulating their physiology to an extent that would sig- altitudes for the hematological module; and some in-
nificantly impact their performance and health. We formation regarding the conditions of sample collec-
foresee the implementation of a Rule of Sport in which tion, transport, and analysis are also stored in the pass-
the athletes who have demonstrated unnatural devia- port for improved decision making (7, 22 ). As such,
tions in physiology would be temporarily withdrawn the ABP becomes a platform for the evaluation of mul-
from competition to allow a period for return to nor- tiple pieces of scientific evidence (15 ), which is similar
mal physiological levels or initiation of appropriate to a forensic approach.

972 Clinical Chemistry 57:7 (2011)

The Athlete Biological Passport
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Toward a Global Forensic Antidoping Policy

Similarly to forensic identification science (26 ), the

strength of the ABP is that it relies on sound empirical
testing in large populations by use of justifiable proto-
cols. The decision support system that is used routinely
to interpret the biomarker data stored in an ABP heav-
ily relies on Bayesian inference techniques (7, 11, 14 –
15, 17–18, 22 ) (Fig. 2). Every element of information
that constitutes doping evidence can be incorporated

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into other elements and/or corroborated by additional
evidence. For example, the result of traditional drug
tests, such as the detection of rEPO in urine (27 ); some
characteristics of athletes, such as a particular genotype
(28 ); and the longitudinal monitoring of individual
performance (29 ) are evidentiary values that can be
incorporated into the ABP decision support system for Fig. 2. Hierarchical graphical Bayesian network (BN)
improved detection of doping. [Taroni et al. (32 )] for the evaluation of the T/E
The ABP introduces a new form of doping evi- marker of steroid doping [Sottas et al. (7 )].
dence and, as such, paves the way for a more global and The T/E is the ratio of the urinary concentrations of testoster-
integrated fight against doping. In particular, we fore- one glucuronide and epitestosterone glucuronide. Each node
see a global forensic approach in which multiple pieces represents a variable (circle, continuous; rectangle, discrete;
of evidence, not restricted to those in the current test- solid, observable; dashed, nonobservable). Arcs represent di-
ing paradigm, are used to demonstrate the culpability rect relevance relationships between variables, with a condi-
of a suspect. For example, the drug enforcement agen- tional probability table associated to each variable. In the BN,
cies and customs departments of many countries seize probabilities of the states of the variables are updated upon
large quantities of doping substances with investiga- the receipt of new evidence. The hidden variables mean (␮)
tions that target illicit drugs, manufacturing compa- and CV adaptively integrate information coming from a series
nies, and trafficking networks. Until recently, the lack of individual T/E values. The heterogeneous factors age and
of collaboration between governmental, public, and sex are set up to take into account differences in steroid
sports authorities has hindered the combination of an- excretion; for example, that females have lower and more
alytical and nonanalytical evidence in many countries. variable urinary T concentrations than males. Significant in-
In the current fight against doping, a customs agency terindividual differences observed in T excretion are associated
can learn that a top-level athlete has received some with a deletion mutation in the UDP glucuronosyltransferase 2
rEPO by mail before an important competition, but family, polypeptide B17 (UGT2B17) gene [Schulze et al. (6)].
this information is not shared with sports authorities, The introduction of genetic variations in the BN make athletes
so that the athlete is still permitted to participate in that missing both copies of the gene, a common trait in Asians,
competition. Interestingly, the methodology devel- equal to those having 1 or 2 copies, a common trait in whites
oped for the ABP provides the necessary framework to and Africans. Interestingly, the knowledge of the individual’s
combine evidence gathered by sports-testing organiza- genotype is unnecessary. Only the characterization of the
tions with nonanalytical evidence gathered by public phenotype is necessary, because the genotype can be inferred
law enforcement agencies. For example, knowledge from the phenotype T/E and from the unusually high degree of
that an athlete received some rEPO by mail can be com- geographic variation in the UGT2B17 gene [Xue et al. (33)].
bined with the information stored in the ABP to eval- There is no conceptual limitation for the application of such
uate whether the athlete used that substance before BNs for the evaluation of any biological marker. The incorpo-
competition. As such, we do not foresee any scientific ration of heterogeneous factors, gene profiles, and longitudi-
limitation for a global fight against doping that is based nal data allows the elimination of interindividual differences
on various sources of evidence. so that the decision can be tailored to the attributes of a single
individual.
Perspectives in Medical and Pharmaceutical
Applications
has mostly relied on the use of population-based refer-
Recent medical practice has relied on standards of care ence intervals and has largely ignored individual differ-
that are based on epidemiologic studies of large co- ences. This situation is particularly problematic be-
horts. In particular, the interpretation of biomarkers cause most biomarkers present significantly higher

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Fig. 3. Steroidal passport of a white male athlete tested on 9 occasions, for 4 markers of steroid doping: T/E, the
ratio of testosterone to androsterone (T/A), the ratio of androsterone to etiocholanolone (A/Etio), and the ratio of
5-␣-androstane-3-␣,17-␤-diol to 5-␤-androstane-3-␣,17-␤-diol (5␣/5␤).
Blue lines represent actual test results. Red lines indicate individual limits. Color bars indicate sequence (seq) abnormality
[Sottas et al (22 )]; prob, probability. The lack of any abnormality indicates that such steroid profile is typical of a normal
physiological condition.

inter- than intraindividual variations. In practice, phy- in the evaluation of biomarker data can be used in some
sicians evaluating an individual patient generally take applications of personalized medicine for improving
into account heterogeneity macrofactors, such as age healthcare. This evaluation was performed for several
and sex. In addition, contemporary advances in omics practical applications in patient monitoring and the
technologies have permitted information concerning a assessment of drug safety and efficacy in clinical trials.
patient’s protein, gene, or metabolite profile to be in- In patient monitoring, the actual frequency and doses
creasingly used to improve healthcare. A longitudinal of a treatment are tailored according to a patient’s in-
record of such profiles is an invaluable tool that can dividualized need for medical care, which is often eval-
assist physicians in their work, such as in oncology, uated from biomarker data. For example, the measure-
wherein early diagnosis is critical to patient outcome. ment of glycohemoglobin, which is a marker of the
The incorporation of heterogeneous factors, use of in- degree of glucose metabolism control, is crucial in
dividual protein or gene profiles, and use of a longitu- making treatment decisions in patients with type 1 di-
dinal approach have the same goal, which is to elimi- abetes. In a second example, cytostatic chemotherapy
nate interindividual differences and tailor medical care doses are determined according to various biomarkers
to an individual’s needs. To achieve the goal of person- and other patient-related factors, such as body surface
alized medicine, any advances in proteomics and other area. In all of these cases, the decision is complicated by
related fields must be captured by decision support sys- various factors, including: variations in laboratory test
tems to facilitate their use in the clinic (30 ). results; information that accrues throughout treat-
Several pharmaceutical companies have contacted ment; heterogeneity in factors, such as age, gender, and
us to evaluate how the knowledge acquired for the ABP body size; narrow target ranges that must be refined for

974 Clinical Chemistry 57:7 (2011)

The Athlete Biological Passport
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every individual in terms of safety and quality of life; health protection in elite sports. In that context, the
and biological variations among individuals. Similar ABP represents the new paradigm in detection of
issues occur in clinical trials, wherein the safety and doping-triggered physiological changes in elite sports.
efficacy of a drug treatment are often evaluated by us- Doping biomarkers provide a means to deter the ath-
ing longitudinal biomarker data. Adaptive Bayesian lete from using performance-enhancing drugs that will
clinical trials have been proposed to adapt to informa- lead to deviation from natural baseline values. In con-
tion that accrues during a clinical trial (31 ). Interest- trast to a drug test that returns a result for a precise
ingly, the support system developed for the ABP puts moment in time and does not have any memory or
all of these concepts into practice and will find a direct perspective, the presentation at the beginning of com-
application in patient monitoring. In retrospective petitions of an ABP that demonstrates normal longitu-

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data provided by pharmaceutical companies, we have dinal profiles will allow athletes to objectively demon-
found that the knowledge of sources of variations (an- strate that they will participate in an unaltered
alytical and biological) is not often taken into account, physiological condition clear of any doping suspicion.
and the development of an ABP-inspired decision sup- Scientists are developing methods that provide an un-
port system improves the decision in all of the afore- equalled opportunity to ensure fairness and the protec-
mentioned applications. In clinical trials, we have tion of health in elite sports; worldwide ABP imple-
found that either the number of patients or the sample mentation is now at the discretion of antidoping
size to fulfill the requirements of the trial could have organizations. The same paradigm can be used in the
been significantly decreased, or that the trial could clinics so that personalized medicine will not only be
have been stopped substantially earlier. In both cases, centered on the deeper molecular makeup of each pa-
the application of the ABP decision support system tient, but also on an interpretation of existing biomark-
could have improved the cost-effectiveness of drug de- ers tailored to each individual.
velopment, resulted in an earlier decision, and helped
patients to receive better treatment.

Conclusions Author Contributions: All authors confirmed they have contributed to

the intellectual content of this paper and have met the following 3 re-
quirements: (a) significant contributions to the conception and design,
Although drug tests have been remarkably successful in acquisition of data, or analysis and interpretation of data; (b) drafting
the detection of synthetic doping substances, the recent or revising the article for intellectual content; and (c) final approval of
availability of doping substances identical to those nat- the published article.
urally produced by the human body demonstrates the Authors’ Disclosures or Potential Conflicts of Interest: No authors
limits of this testing paradigm to ensure fairness and declared any potential conflicts of interest.

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