Athlete Biological Passport: Need and Challenges

Abstract

The Athlete Biological Passport programme was initiated in 2009 by the World Anti-Doping Agency for making the anti-doping programme more effective and stronger. There are three modules in this ABP programme: haematological, steroidal and endocrinological. Currently, the first two modules have been implemented. The newer products such as recombinant human erythropoietin, recombinant proteins, and peptides are similar to those produced naturally. Hence, detection of these substances even with advanced techniques is difficult. Therefore, the concept of ABP came into existence which is based on longitudinal monitoring of biological markers and their variations over a period of time. The ABP does not rely upon the detection of a particular prohibited substance but it reflects the changes in biological markers collated over an athlete’s career. Hence, athletes can be monitored through constant interpretation of the passport data. There are many advantages with the implementation of this programme; however, there are various issues which may lead to false interpretation of passport data that must be taken into consideration.

Introduction

The term "Athlete Biological Passport" was first suggested by the scientific community in the early 2000s when monitoring of selected haematological variables (blood doping markers) was established as a way of determining the haematological profile of an athlete. The World Anti-Doping Agency (WADA) started further establishing, harmonizing and validating the definition in consultation with several stakeholders and medical experts. The result was emergence of standardized operational guidelines and mandatory requirements known as the athlete biological passport (ABP) in 2009, specifically for the haematological section. In 2014, the steroidal module was added to the initial system, which was initiated to establish longitudinal profiles of an athlete’s steroid markers. The framework implemented in these guidelines adds to the current anti-doping infrastructure thus improving the efficiency of anti-doping practices [1].

Many international sports federations have decided since the 2006 Torino Winter Olympic Games that WADA will harmonize the development and evaluation of the ABP programme. There are three distinct modules of the ABP programme: haematological, steroidal, and endocrinological modules [2]. The introduction of haematological module was done in December 2009 whereas the steroidal module was introduced in 2014 [1]. The endocrinological module may be operational in the near future.

National Anti-Doping Agency of India has started the athlete biological passport programme only for the athletes who are going to represent the country in the Tokyo Olympics which are going to be held in 2020. Expanding this programme for other national and state level athletes will be done soon [3]. A symposium was also conducted by NADA officials for various medical experts from leading medical institutes like All India Institute of Medical Sciences, Safdarjung Hospital and Dr. Ram Manohar Lohia Hospital for expanding the knowledge about this programme [4].

History

Sports authorities all over the world strive to make the sporting activities dope free, healthy and genuine. Until now the primary methods for checking the substance abuse in athletes is detection of banned substances in various body fluids most commonly urine and blood. Techniques like chromatography and mass spectrometry have grossly increased the range of compounds that can be detected. The newer compounds that are used to enhance performance are mostly recombinant proteins, peptides that are similar to those naturally produced in the body. Hence, even with latest techniques, the detection of these new performance-enhancing compounds is practically impossible. Therefore, alternative strategies were developed for maintaining the integrity of the sport [2].

For many years, the idea of human biological marker monitoring was explored for identifying the usage of prohibited drugs [5]. When recombinant human erythropoietin (rh-EPO) was launched, the concept of longitudinal tracking was developed quite soon. When endurance athletes’ misuse of rh-EPO increased rapidly during 1990s, several suggestions for indirectly measuring the biological markers were proposed [5].

So, the concept of the “athlete biological passport” (ABP) came into existence which detects the variation due to the use of banned substances through the longitudinal tracking of these biomarkers.

Objectives

It can be utilized for insightful, timely analysis of passport information to identify athletes who need more attention. It provides important information that can be used to efficiently guide target evaluation or investigation. It may be useful as a complement to analytical methods to refine and reinforce overall doping control activities [1].

It may also be used to prosecute a violation of the Anti-Doping Regulation (ADRV) according to Article 2.2 of the World Anti-Doping Code 2015. By looking at the differences in the biological markers for doping accumulated over the career of an athlete, it can be used to determine' use' through Article 2.2 of the Code and not actually depending upon the identification of a single prohibited substance or procedure. This procedure has proved to be successful in proving violations without the need for conventional approaches [1].

Modules

Haematological Module

This module gathers the details about blood doping markers. The purpose is for identifying the usage of banned substances and methods to improve O₂ transportation, which includes the usage of erythropoietin stimulating agents and any sort of transfusion of blood or blood products. Besides the identification of the usage of erythropoietin-stimulating agents listed in section S2 of the Prohibited List, the haematological module also aims to classify the usage of prohibited methods identified under section M1 of the Prohibited List (Blood and Blood Products Manipulation) [1].

For measuring the concentration of biological markers in blood (e.g., haemoglobin), the key confounding factor is the potential impact of differences in plasma volume. However, the changes in haemoglobin cannot only be as a result of doping by increasing the quantity of the molecules in circulation, but also by altering the fluid component of blood, namely the volume of plasma. These fluctuations in plasma volume are caused due to physical activities or surrounding conditions, like temperature or altitude, any factors producing stress to which high-performing athletes are frequently exposed. In future, fixing passport markers for these differences will be a vital task [6].

The incorporation of new markers in the haematological system is a challenge. Given the strict criteria for including a marker for longitudinal tracking, there are currently only a few variables for which longitudinal tracking is possible and almost all of them contribute to the metabolism of iron. Further research is required before any of these iron metabolism markers are incorporated [6] (Fig. 1).

Fig. 1.

This is a hypothetical graph of an athlete’s haemoglobin concentration measured over time and monitored under normal conditions. The blue line indicates the upper reference range, whereas the grey line indicates the lower reference range of the individual calculated with the help of software. The red line indicates the measured values. The same kind of graph is constructed for other markers also. It is suggested that samples obtained 5 days apart or more should be used for the data analysis of the haematological module parameters to maximize the statistical significance of the data [1]

Steroidal Module

This module gathers data regarding steroid doping markers. The main aim is the identification of endogenous anabolic androgenic steroids when given exogenous and other anabolic agents, such as selective androgen receptor modulators grouped under Section S1.2 of the Prohibited List. Additionally, it is effective for identifying sample that may be contaminated or mixed with another person's urine [1].

Endocrine Module

The ABP steroidal module can identify several direct or indirect types of steroidal doping, but it does not detect certain growth factors, such as growth hormone and insulin-like growth factor, which is the target of this module [2]. From the beginning of the 1980s, GH was abused in sports at a time when "cadaver GH" was extracted and refined from pituitary gland derived from corpses. It was one of the first hormones which was developed using recombinant DNA technology in 1985. Anti-doping test was first developed in the mid 2000s, based on recombinant GHs degenerated isoform pattern [6, 7].

Athlete Passport Management Unit (APMU)

In the passport process, the Athlete Passport Management System plays a significant role. This department, usually tied up with the anti-doping laboratories, is responsible for the administrative side of the respective passport programmes to ensure fair and impartial evaluation of the passport results and eligible follow-up. It offers resources for tailored screening and correct test schedule, maintains laboratory data, assembles analytical reports, carries out initial reviews, and cooperates for an in-depth assessment of passport information between anti-doping organisations (ADOs) and independent experts. The APMU must report to the anti-doping agency about any adverse passport results. APMU personnel must have proper knowledge for administering and managing the anti-doping activities inclusive of legal side. The knowledge of pre-analytical and diagnostic protocols as well as exercise physiology is also very important for ensuring that the tests are well planned in each athletic discipline based on the predicted effects of the most common abused substances [8].

The APMU shall engage the services of qualified experts for the review of passports.

• The basic requirement for the expert panel of haematological module is three experts who are qualified in the fields of:

  • Clinical and Lab haematology
  • Sports medicine
  • Exercise physiology
• And for steroidal module is three experts who are qualified in the field of:

  • Lab steroid analyzer
  • Steroid doping and metabolism
  • Clinical endocrinology

• It is mandatory that the board constituted for reviewing any passport’s data, no two specialists shall be of the same nationality and should not be having a primary connection with same corporation.

• Out of all the specialists, one must be presently a member of WADA affiliated management unit or must have served earlier in a WADA affiliated management unit [9] (Fig. 2; Table 1).

Fig. 2.

Administrative sequence of athlete passport management unit [1]

Table 1.

List of athlete passport management units associated with WADA accredited laboratories (as per the 2019 list) [10]

Australia

Austria

Belgium

Canada

China

France

Germany

Great Britain

Italy

Japan

Norway

Poland

Qatar

Spain

Switzerland

United States of America

The authorization of APMU can be suspended or cancelled if it does not follow the relevant rules or when this kind of action is required for protecting the interests of the anti-doping community [9].

Challenges

Haematological module of ABP has been adopted by 48 anti-doping organisations to enhance the effectiveness of doping control programme [11]. Since the implementation of ABP, there has been a significant decrease in reticulocyte percentage which is a marker of blood doping [12]. This indicates that introduction of ABP has had a deterrant effect.

ABP includes many haematological variables and these various haematological variables are influenced by several external and internal factors like ethnicity, age, sex, analyser used for measurement, type of sport, effect of seasonal changes on the haematological parameters and exposure to altitude [9]. Out of all the many external factors which may influence haematological variables, the exposure to altitude is not standardized [13]. The various detection models still do not address the issue of time course required for normalization of different variables after being exposed to high altitude [14]. For proper standardization, different altitude/hypoxic protocols should be considered. Surprisingly natural and artificially induced hypoxic conditions have produced different outcomes. One of the examples in which altitude training lead to suspicious blood profiling is of Italian elite cyclist Franco Pellizotti who was banned under the ABP program [15, 16].

Since the adoption of haematological module, several issues regarding analytical variation in testing have been seen [17]. The stability of blood parameters used to determine ABP has been found to be influenced by several factors and these factors may influence vascular volume [18]. For example, haemoglobin concentration shows significant variations due to physical activity or diurnal variation as the plasma volume expands following regular physical activity [19]. Hence, before using the indirect markers for detecting the positive cases, these details need to be considered [20].

Administering recombinant human erythropoietin (rHuEPO) followed by hypoxia therapy modifies the haematological variables therefore masking the use of rHuEPO by athletes causing difficulty in detecting the misuse [21]. Similarly, desmopressin has shown to have a haemodilution effect leading to significant reduction in the values obtained [22]. Thus, these strategies must be considered before making any conclusion.

If the genetic information would have been incorporated in the ABP programme, it could have been useful in a few cases like of Eero Mäntyranta case. He won multiple medals during the Olympic Games with a significant gap which could be because of rigorous trainings he undertook or maybe because of the determination, but his haemoglobin levels were more than 60% higher than the standard suggestive of doping. Actually, the levels were higher due to a mutation in a gene leading to an increase in RBC precursors. According to the guidelines, the changing of the variables within an individual must be in a small range than for a population having the same age and sex but due to the mutation in this case the levels were at a higher level all time [23].

As the databases include personal details of an athlete, so access to data and maintenance of data confidentiality are some of the concerns which are to be stressed upon. The most relevant question in this regard is should the data be accessible to the athletes? Allowing the data to be accessible to the athletes which is currently being practiced can give the athlete a chance to monitor his/her parameters. First, disclosing the data may allow the athlete for monitoring the regime thus promoting the development of other methods. Second, it can result in an athlete being discriminated against or being targeted. Also, the staff of various teams may also manipulate the athlete for providing their ABP-related information while negotiating agreement. Hence, giving the athletes access to raw data may jeopardize the very purpose of this programme [24]. According to WADA the only aim for this programme is to assist in combat doping and no way is it an instrument for medical check up or keeping track of one’s health [1]. Currently the haematological data is accessible and not of the steroidal module [25].

Another challenge for APMU may be a form of pregnancy doping which is defined as the female athlete’s misuse of pregnancy and with the help of coaches and support staff artificially inducing physiological benefit, increasing RBCs mass and enhancing the transportation of O₂ which ultimately leads to increase in the performance [26]. The activity of women during the pregnancy is high mostly in the first trimester, so studying the steroid profile in pregnant women is important. The reference range which was measured is prone to minor changes. Previous research showed huge intra-individual variation in ABP ratios, being more evident in women [27, 28]. The menstrual cycle and contraceptive use were found to have an impact on concentrations of urinary epitestosterone [28, 29]. A study showed that the steroid profile is affected by pregnancy and can therefore lead to atypical finding. Such atypical results will result in needless confirmatory procedure unless the APMU recognizes the pattern of pregnancy [30].

Conclusion

Unlike the traditional testing procedures where the presence or absence of drug or its metabolites determine the positivity or negativity of the test, in ABP knowledge of an expert is required for evaluating the profile due to which subjective component comes into play, as based upon their evaluation it will be decided that whether the test was positive due to the use of a banned substance or due to another cause. The test should be done during the time when manipulation of the profile is most probable and also during the time when it is normal for demonstrating the anomalies clearly. It is important for this programme to provide the proof of the doping scenario clearly for taking appropriate action under NADA and WADA [8].

Abbreviations

ABP

Athlete biological passport

ADAMS

Anti-doping administration and management system

ADOs

Anti-doping organisations

ADRV

Anti-doping rule violations

APMU

Athlete Passport Management Unit

GH

Growth hormone

Hb

Haemoglobin

NADA

National Anti-Doping Agency

RBC

Red blood cells

rh-EPO

Recombinant human erythropoietin

WADA

World Anti-Doping Agency

Funding

No funding has been obtained for this article.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Informed consent

For this type of study informed consent is not required.