What should you think about Lance Armstrong's positive EPO test?

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Urine samples from Lance Armstrong during the 1999 Tour de France have tested positive for EPO EPO. Naturally, Armstrong denies it, but Richard W. Pound, the chairman of the World Anti-Doping Agency says:
"There's not much of a middle ground, is there?" said Richard W. Pound, the chairman of the World Anti-Doping Agency. He added that it appeared that the "tests show there was EPO there" and that the EPO test was "as close to 100 percent reliable as you could get."

Reading the original papers on which the test is based gives you a rather different picture, however. Moreover, reading on in the article we find out that there are studies claiming to show false positives in urine from athletes who have been engaging in strenuous exercise.

Background
Erythropoietin (EPO) is a hormone that stimulates red blood cell production. Because anemia is a common medical problem, synthetic (recombinant) versions of EPO have been developed by serveral pharmaceutical companies. However, EPO also has a use as a performance enhancer. Up to a point, the higher your red blood cell count, the higher the oxygen carrying capacity of your blood and the better your endurance performance. Unsurprisingly, it's become relatively common for endurance athletes to use EPO as a performance enhancing drug. Because rHuEPO is the same protein as EPO it's very difficult to distinguish individuals with normally high EPO levels from individuals who have been doping. And since one would expect endurance athletes to have very high hematocrits, this makes doping very hard to detect.

In 2000, Lasne, et al. invented a test that allegedly distinguished natural human EPO from rHuEPO. The test took advantage of the fact that although the protein sequence of natural EPO and rHuEPO is the same, the glycosylation is not. The test uses isoelectric focusing (a form of gel electrophoresis). rHuEPO produces a characteristic banding pattern on the gel that's different from natural EPO.

L'Affaire Armstrong
EPO use has been endemic in professional cycling for years, especially before a reliable test was developed. Rumors have long circulated that Lance Armstrong was using EPO during his TdF races (it's known that he used it during his cancer treatment and there's nothing wrong with that). However, even under the very strict TdF testing regime, Armstrong has always tested clean.

Last month, in what appears to have been part of a research program, the same French lab that developed the original EPO test retested a bunch of frozen urine samples from 1999 and at least a dozen of them tested positive for rHuEPO. The matter would have ended there except that somehow a reporter from L'Equipe obtained a copy of the results and the key that matched the samples to athletes. He claims that six of the samples were Armstrong's.

Reasons for skepticism
Assume for the moment that there wasn't any hanky-panky (mislabelling, contamination, etc.) in the sample handling. Should you conclude that Armstrong was doping in 1999. After going over the sections of the literature I was able to get my hands on I think the answer is no, for three reasons.

I haven't been able to find any estimates of the error rates of the test procedure. If you read theoriginal Lasne paper, the difference between rHuEPO and natural EPO is quite striking, but Lasne et al. don't report any statistical experiments that would let you estimate the false positive or false negative rate. I can't even figure out how many samples they used. A followon study by Khan et al. describing an improvement on this technique used a single pair of donors, so it's possible that the sample size wasn't large enough to provide an adequate baseline. A World Anti-Doping Agency report (by Peltre and Thormann) appears to describe problems in the original Lasne technique, but it's been removed from the WADA website so I can't say for sure. This isn't comforting.

The second problem is the long storage time of the samples, which were taken in 1999. My biochemistry is a bit rusty, but it seems possible that long storage could lead to chemical reactions that produce other isoforms. I don't see any evidence that anyone has done a controlled trial to determine whether this could lead to false positives. This seems like a topic that would be relatively easy to study, provided we have the archival samples.

The third, and most serious, problem is that there appears to be direct evidence that the Lasne test produces false positives. The Flemish triathlete Rutger Beke tested positive for EPO, but according to the Times article, it has been shown that when under heavy training loads he produces positive results without having taken EPO (see here) His suspension has been lifted.

Bottom Line
Note that I'm not saying that Lance Armstrong wasn't taking EPO. It's certainly possible that he was. Unfortunately, the available testing methodology doesn't appear to be good enough to let us differentiate the possibility that he is from the possibility that he isn't. Based on the studies I've read, it's not even clear that the testing methodology is really adequate to distinguish cases of current usage when the samples have been stored properly.

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6 Comments

Well, there are certainly different standards of proof, and I'm prepared to believe that Armstrong can't be proven guilty by the standards of a court of law, or the reigning sports body, or maybe even a scrupulous journalist. But on a blog, surely the standards are different--no? Between you, me and your readers, if you knew that the provably correct answer to the question, "did Lance Armstrong use EPO illegally?", were to be revealed in a week's time, would you even need favorable odds before happily betting that the answer will be "yes"?

Well, since a standard of proof is mostly just a probability threshold, it's always legitimate to ask what one's probability estimates are. It seems to me that there are actually (at least) questions here:

(1) What's my a priori probability that Lance Armstrong used EPO illegally?

(2) Given this new data, what's my new estimate that Lance Armstrong used EPO illegally?

I suspect that if I was pushed (I.e., I had to take one side or the other of the bet) my answer to (1) would be over 50%. I'm actually having trouble estimating the answer to (2). The testing methodology seems so sloppy and the provenance of the samples so unclear that it's pretty hard to know how seriously to take it. And since I prefer to say I don't know than to take a position and be wrong....

Also, one factor which would lower the probabilities: In the post-EPO testing era (2000-2005), Lance Armstrong continued to win, win, and win.

Unlike baseball, where suddenly the sluggers aren't hitting, or are on the DL, etc etc etc...

There has been considerable mention in the press of so-called A and B samples. Can you shed any light on what this means and what the implications would be for the accuracy of the test?

Also, don't Armstrong's critics claim that he continued to use EPO in his more recent TdF races? If so, how is he supposed to have evaded detection?

It is completely unreasonable to Assume for the moment that there wasn't any hanky-panky (mislabelling, contamination, etc.) in the sample handling. The fact that the samples were used at all, when they should have been destroyed after the A samples were found negative, shows that the lab is willing to fudge on procedures.

Further, it is trivial to change sample numbers on vials over the course of many years, particularly on vials that no one is paying attention to for long periods of time. If I didn't like Lance, and I had a bunch of samples from people who I assumed were more likely than he to have cheated, there would be no downside to me switching labels.

The fact that the science has yet to get good enough to prove that an old same did or did not indicate cheating is reason enough for the lab itself to cheat and get positive publicity (at least in its own country) for "discovering" something.

Paul,

I agree that there clearly was something fishy about the handling of the samples. But for the purposes of discussion, I'm interested in the scientific issues only....

Hal: They collect A and B samples and test only the A. If the A is positive they have an undisturbed sample that can be tested for confirmation.

Yes, it's true that Armstrong has repeatedly tested negative. OTOH, the false negative rate of this test is high so there's a possibility that he could have been evading... Or, he cheated when it was easy and then when nobody could cheat, he stopped too, and since he is better overall... Or, he could just be clean. A complicated issue.

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