Tuesday, October 09, 2012

Scientists' Debate: Parisotto's Closing Arguments

After a break for our Medtronic TCM Marathon coverage, we have reached the point of "closing arguments" in the scientific debate between Robin Parisotto and Dr. Michele Ferrari regarding what may be a small piece of the file USADA will soon send to WADA and UCI regarding the doping conspiracy case they pursued on cyclist Lance Armstrong.  The debate began with Parisotto's original analysis of some of the data (HEREArmstrong had published on his website during his comeback to cycling in 2009 and an invitation to readers to "peak behind the curtain" of  the process of deciding guilt or innocence in a doping case HERE and HERE.

That was followed by a debate between Parisotto and Dr. Ferrari in several installments  beginning  HERE and proceeding with the point/counterpoint  HERE HERE, HERE, and HERE. Below are Parisotto's "closing arguments."  Dr. Ferrari may post his after reading the remarks below and we'll post a link to them if and when he does.  

Thanks to both Parisotto and Dr. Ferrari for allowing us to be spectators in the debate and get that "peak behind the curtain" of the biological passport process and the spirited exchange of information that transpires in these cases.---Jim Ferstle

Response to Dr. Ferrari from Robin Parisotto
First, it must be asked how a member of the public (as Armstrong has stated, Dr. Ferrari is merely a friend and their conversations during his comeback in 2008-2010 were not  about matters of training or physiological analysis such as this) has such intimate knowledge of times, places, and conditions surrounding the blood tests. 

By posting the results on the web it could be argued that Armstrong had invited speculation and perhaps should have provided other relevant information (which Ferrari appears to have at hand) for others to consider as well. Much of this debate Dr Ferrari and I have engaged in only involves the initial phase of a case brought using the biological passport. 

For example none of the data and the information that Ferrari claims to have or know about is verifiable at this point. Meaning that a higher standard of proof applies in making decisions in a biological passport case.  Any action that is taken has to be the result of the analysis of  all the relevant data available to the panel studying the case and creating an official Biological Passport profile. 

While Ferrari may be intimately aware of the Passport guidelines/rules etc.,  it cannot be assumed that everyone else is also. This is critical if readers are to understand both his position and mine. For example, as Dr. Ferrari argues, whether an athlete’s values lie within the predictive value (for upper and lower levels) is irrelevant in the context of the passport. 

It is the variability of measures, the magnitude of the changes, and the timing of the changes that are key to forming an opinion. When an athlete's data shows wide variation in blood values breaching the upper and lower limits, however, this does raise a "red flag," and influences the recommendation made using that data.

When an individual athlete's Biological Passport is assessed, it is classified into one of four categories; normal, target, pathology and doping suspicion.  (Normal means there are no suspicious values.  Target means there are suspicious values, but more data is needed so the athlete is "targeted" for further testing.  Pathology means there may be other indicators that a disease or other medical issue may be responsible for the abnormal blood values.  Doping suspicion is a case where the values are consistent with known physiological responses to using doping substances or methods.)   

It is not uncommon that an initial evaluation of the data received to result in a classification as a doping suspicion. But the case doesn't end there, it has to survive much more analysis before it moves from being a suspicion to the recommendation that it be adjudicated as a doping violation.

Following the initial evaluation, full documentation packages are provided in order for experts to assess the influences of competition status, environmental conditions, time and place of collection, transport and storage conditions, and analytical techniques/controls. 

So in responding to Ferrari’s claim of pre-emptory accusation "subjectivity," it is "subjective" in the sense it is being done by people who will form opinions on the data, but in order to get beyond the initial stage of "suspicion" to "possible/probable" doping violation, that conclusion must be supported by the data, not a subjective belief that the initial data might be evidence of doping. 

The real test of any conclusion is a second and third opinion followed by a teleconference review and report, and then a full evaluation of documentation packages by three separate experts who must all agree and sign off the findings/conclusions in a comprehensive report. The athlete is then afforded the opportunity to counter –argue the panel members evaluation(s) before a final recommendation for sanctioning (or not) is made.

It is evident therefore that a final recommendation to proceed to sanctioning is made on the ‘balance of probability’ that the evidence suggests/supports a suspicion of doping. This is made following considerations given to any influence of competition, altitude exposure, illness/injury etc as I have previously stated. The decisions are not made lightly nor without due diligence and due process.

With regards to Hemoglobin levels during competitive racing,  it is a well known that the body responds by increasing plasma volume during long racing events, such as cycling stage races(Tour de France, etc). An increase in blood volume is one of the basic physiological adjustments which the human body makes in response to endurance training/performance.  This helps the body to dissipate heat by shifting fluid from the tissues into the circulation passing through the capillary blood vessels into the skin for cooling. 

This response also decreases blood viscosity and improves blood flow resulting in reduced heart rates and more efficient delivery of oxygen to the muscles, all of which are beneficial attributes for endurance performance. In doing so, the formed or cellular elements in the circulation like red blood cells will therefore be artificially reduced and this scenario continues until physical activities have ceased. 

So when the cellular elements(Hemoglobin, etc.) in the circulation increase rather than decrease as expected (which is well documented in the literature) during the course of a long race, it may be a sign of manipulation; the infusion of ‘extra’ blood comes to mind. This can be corroborated by what’s happening with the young red blood cells (reticulocytes).  If Hemoglobin is truly increasing,  then it follows that the reticulocyte levels will also increase. 

With regards to the reticulocytes Ferrari states;
The reduction in reticulocytes (around 0.2%) evoked by Parisotto is not significant: the average value of the six tests during the TdF 2009 is 0.61%, which is perfectly compatible with a previous period of 26 days at altitude. Just as the reticulocytes in the tests dated 16th and 17th of June (0.64 and 0.74), collected after 16 days of altitude-induced hypoxic stimulus, correspond to a slowdown in the hematopoietic response subsequent to the increase in the concentration of Hb (16.0)’

I will let readers ponder the following..  What are the causes of decreased red blood cell production and why would this persist long after return from altitude? Does the reduction in reticulocyte values during the 2009 Tour reflect a continued slowdown in the hemopoietic response(the natural response of the body to try and maintain homeostasis or equilibrium)?  Following return from altitude exposure the body would be busily restoring hemopoietic balance by producing more reticulocyes so that  the body is not deprived of much needed red blood cells to support extreme physiological efforts. 

Thus if you see high hemoglobin levels combined with low reiticulocytes in a person's blood, you have to ask: If hemodilution does not affect the reticulocyte levels what may be the reason(s) for the prolonged shutdown of red blood cell production?

There are a number of causes which result in the shutdown and/or decrease in red blood cell production:
1.    Due to diseases such as Aplastic Anaemia, congenital red blood cell disorders such as Diamond Blackfan syndrome etc
2.       Travel into outer space – gravity inhibits the release of new red blood cells and/or destroys new red blood cells entering into the circulation in a process known as neocytolysis, or more simply the death of new blood cells (for those with a propensity to laugh at this suggestion see PubMed article by Alfrey C and Rice L 2000)
3.       Micro-doping with EPO/CERA etc
4.       Previous doping with EPO/CERA etc
5.       Previous blood transfusion  

If the first two causes are eliminated by the thorough evaluation of athlete medical records and ‘travel history,’ then we are left with the possibility of doping.  The only remaining question then is by what means (3, 4 or 5 above).  

While Ferrari contends that Hemoglobin concentration may be affected by training, fatigue, rest, stress, nutrition, hydration, and altitude, this cannot be said of the percentage value for reticulocytes. In a situation where Hemoglobin is increasing despite an expected physiological response to decrease due to plasma volume expansion and the reticulocytes are decreasing (or have remained static) this just does not "compute." It is a physiological oxymoron in a normal healthy athlete, especially one who has been able to place third in arguably the world’s toughest endurance event.

Finally, with regards to concerns that the Biological Passport is too subjective to differentiate doping from physiological disturbances, to date 25 cyclists have been sanctioned as a result of ‘targeting’ due to evidence gleaned from the passport which subsequently led to positive tests for exogenous stimulating agents such as EPO and CERA.   Another four athletes were sanctioned simply on the basis of suspicious profiles. A further eight track and field athletes have also been sanctioned on evidence from the passport alone, and the number of cases decided through use of Biological Passport data will continue to mount.

The Biological Profile and this "data mining" approach to uncovering "sophisticated dopers" was not being used effectively by all federations back in 2008-2009.  While it is natural to question whether or not a new system is "robust" enough to handle the burden of providing conclusive proof to back up the rampant suspicions of doping, the ability to successfully investigate and adjudicate doping cases, as noted above, indicates that is a valuable tool in detecting and sanctioning the more sophisticated dopers, not a tool for targeting specific athletes in overzealous attempts to spend time, money, and resources on "witch hunts." 

My judgment on the data we have been presented with remains that, upon initial evaluation in the Biological Passport process, this case would be classified as a Doping Suspicion.  Irrespective of this debate though the file in the Armstrong case that will include the evidence collected and used to bring it to prosecution will be handed over to WADA and the UCI by USADA.  The evaluation of the file data by these organizations will determine the outcome of the next step in the process.  Hopefully that file will be made public as well and readers can then make up their own minds.  

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