For thousands of world-class athletes, a passport is something they can't forget to pack before heading off to London for the summer Olympic games. But for a few athletes, a different kind of passport is keeping them out of competition entirely.

A new anti-doping program known as the athlete biological passport (ABP), which looks for indirect evidence that an athlete has cheated, is being implemented by several international sports authorities. Already the testing scheme, developed by the World Anti-Doping Agency (WADA), has ensnared world-class athletes—and survived a challenge to its validity.

The London Olympics mark the first summer games in which the ABP will be in use alongside traditional drug screenings. And for competitors in sports that have taken up the program, such as cycling and track and field, dreams of Olympic glory will depend on their test results—past and present.

Rather than screening an athlete's blood or urine samples for traces of banned substances right before or after a competition, testers using the ABP scheme compare samples with an athlete's baseline profile, as determined by multiple tests over time. In the absence of a legitimate physiological explanation, such as an illness or a natural response to changing altitude, variations in an athlete's biological samples can reveal wrongdoing even if the specific doping agent or process remains undetected. For instance, a sudden change in the number of reticulocytes, or immature blood cells, might provide indirect evidence that an athlete has used erythropoietin (EPO), a hormone that stimulates the generation of red blood cells and boosts the oxygen-carrying capacity of the blood. Similar tests can assess levels of the respiratory pigment hemoglobin, which can also reveal instances of blood manipulation to enhance oxygen transport.

"In this way, the athlete becomes his own reference point," says WADA medical director Alan Vernec. "Otherwise you're forever chasing after new types of substances or agents that are being developed."

So far the biological passport has been applied primarily to detect instances of blood doping, but the same strategy could be used on urine samples to identify users of anabolic steroids. Nevertheless, the ABP is unlikely to supplant conventional testing schemes that detect prohibited molecules, such as steroids or human growth hormone, in blood and urine. Anti-doping experts view the passport approach as a complement to such tests, which continue to catch athletes breaking the rules.

Indeed, conventional testing still plays a significant role in cycling, the first major sport to sign on to WADA's passport approach. In the highest-profile recent case, Spanish cyclist Alberto Contador was issued a two-year suspension and stripped of his 2010 Tour de France win after a sample that year tested positive for clenbuterol, which WADA classifies as an anabolic agent.

The International Cycling Union (UCI), suffering from a severe credibility problem, adopted the ABP in 2008, collecting about 10 blood samples each from more than 800 riders over the course of the year. But implementation of the ABP has not been without twists and turns. Cyclist Franco Pellizotti, who raced for Italy in the 2008 Olympics, was suspended in 2010 for irregularities in his blood profile that indicated "enhancement of oxygen transfer." But the rider was soon exonerated by the Italian Olympic committee, which held that the evidence against Pellizotti was insufficient to prove his guilt.

The cycling union appealed to the Court of Arbitration for Sport (CAS) in Switzerland, which last year overturned the Italian committee's decision and reinstated Pellizotti's two-year ban from cycling. The court also upheld a two-year ban for Italian rider Pietro Caucchioli; the cyclist's variations in hemoglobin concentration over a span of several months, the court ruled, "could not be considered as physiological" and hence demonstrated doping to enhance the blood's oxygen-carrying capacity.

More importantly, the CAS verdict declared the biological passport scheme valid in the eyes of the high court of international sports. The court announced that it "found that the strict application of such [a] program could be considered as a reliable means of detecting indirect doping methods."

The passport concept has also been adopted by the International Association of Athletics Federations (IAAF), the governing body for track and field. In May 2012 the IAAF announced its first suspension based on the testing scheme. Portuguese long-distance runner Hélder Ornelas, who competed in the 2000 and 2008 Olympics, received a four-year ban for abnormalities in blood samples taken in 2009 and 2010. A panel of three hematology experts "unanimously concluded that there was no known reasonable explanation for the abnormalities observed in his blood profile other than the use of a prohibited substance or a prohibited method," according to an IAAF announcement. Ornelas did not appeal the suspension.

The sporting body did not announce what substance or doping method Ornelas was suspected of using, and in fact testers in such cases may never find out what specific tactic the athlete has used to enhance his or her performance. "[ABP] is a game changer because now we don't really care what you're doing to drive up your hemoglobin or play around with your hemoglobin levels, because we're just looking a variation in those levels," Vernec says.

Anti-doping experts view such time-spanning, longitudinal analyses of athletes' biological attributes as an important addition to the anti-doping arsenal. "You can kind of baseline a particular athlete," says pathologist Anthony Butch, the director of the University of California, Los Angeles, Olympic Analytical Laboratory. "They don't vary as much as two different athletes do."

Although the biological passport program is just now edging onto the Olympic stage, the longitudinal analysis of athlete's biological attributes is not entirely new. The U.S. Anti-Doping Agency (USADA)—not part of WADA—for instance, built a 2004 doping case against sprinter Michelle Collins in part on indirect evidence, including years of urine tests that showed "extreme fluctuations" in her testosterone levels. Her unusual pattern of test results, along with e-mail and financial records linking her to a drug lab, led to a four-year suspension from the sport.

The case was notable in part because Collins had never tested positive for a banned substance, but the test results were nonetheless damning when taken together. Even tests that come up clean can turn out to reveal evidence of wrongdoing down the line, notes USADA scientific director Matthew Fedoruk. It is all part of the ever-evolving cat-and-mouse game between anti-doping agencies and drug cheats. "We're trying our best and using a number of different approaches," Fedoruk says.

"I think we have to constantly refine the tool kit," Butch adds. As soon as testers figure out which substances are in use and refine their techniques for detecting them, he says, "the athletes get wise to this and change their modes of use." That is why building a longitudinal profile from test results can be so useful. Butch calls it one facet of "intelligent testing," along with taking athletes' samples at random times out of competition, when a test may not be expected.

With better data from targeted screening and more data from longitudinal monitoring, anti-doping agencies hope that they can gain an edge in the off-the-field competition between drug cheats and drug testers. "Just simply collecting more blood samples and more urine samples is not the answer to this," Butch says. "You have to be smart about when you test and why you test."

Scientists who helped develop the ABP program say that it will be used for several sports during the London games. But just how the passport scheme will work when the International Olympic Committee (IOC) takes over testing efforts from the individual sporting federations and national anti-doping organizations during the competition has yet to be detailed. And its implementation certainly requires more analysis and cross-lab collaboration than conventional, straight-ahead screening of a sample in isolation.

The ABP is "definitely a step in the right direction," says Don Catlin of Anti-Doping Research, Inc., in Los Angeles, who serves on the IOC's medical commission. "It is catching on," Catlin says. "But it's complicated." The ABP model, he adds, is a good one, but "having it work worldwide requires considerable dexterity and coordination of analysis."

Whether or not the ABP scheme uncovers any wrongdoing at the 2012 Summer Games, the athletes can be sure that their biological samples have been closely scrutinized. "You can sort of describe it as the most comprehensive screening and testing that's ever been done in the Olympics," Catlin says.

This year the IOC has the unprecedented benefit of a multimillion-dollar sponsorship from a major drug company, GlaxoSmithKline, which is providing a base of operations near London and laboratory services for the anti-doping effort. "I've done three Olympics, and we've always had a huge budget," Catlin says—but nothing like the resources available this year.

He compares the preparation for an Olympic anti-doping campaign to an athlete's training for the games. "It's the same Olympic model going on with the laboratories," he says. "The labs are training vigorously for four years."

—This article includes reporting by Larry Greenemeier.