Damn you, Kathleen.
Every time I think that I can give the whole mercury/autism thing a rest for a while and move on to less infuriating pastures, you keep finding things that keep dragging me back to the pit of pseudoscience inhabited by Dr. Mark Geier and his son David. The first time around, Kathleen found the Geiers misrepresenting David Geier's credentials on published journal articles to make it appear that David Geier had done the work reported in the articles at George Washington University when in fact he had not. I found David Geier's appropriation of the name of George Washington University distasteful, and said so, elaborating a bit on why such misrepresentations are frowned upon in the world of science. The second time around, what Kathleen reported was much more disturbing to me, namely that the Geiers had formed a dubious (at best) Institutional Review Board to rubberstamp their "studies" involving measuring androgen levels in children with autism based on their scientifically and chemically implausible and unsupported idea that somehow testosterone interferes with chelation therapy because (they claim) testosterone binds mercury and prevents if from being eliminated from the body. (Never mind that the existing scientific evidence does not support a role for mercury in the pathogenesis of autism.) Presumably, if the Geiers are bothering to use an IRB at all to examine it, this is the same IRB that would oversee the Geiers' "Lupron protocol," in which they give a powerful drug that inhibits the production of sex steroids, a protocol that they are trying to patent. Between the patent, the dubious IRB that contained both David and Mark Geier, Mark Geier's wife, anti-thimerosal activists, and a woman whose child was in the Geiers' study, I was beginning to see a pattern, a pattern that, as a medical researcher, I did not like at all.
And the pattern continues, and, my annoyance at being assaulted with yet another example of the Geiers' lack of concern for sound research aside, I'm glad Kathleen is on the case.
This time around, Kathleen reports on how the Geiers are "justifying" their use of Lupron to treat autistic children. All I can say is: Just when I thought it couldn't get worse after the business of the dubious IRB, it gets worse. In this installment, we learn how the Geiers have been publicizing their new "Lupron protocol" among desperate parents who had swallowed the chelation therapy Kool Aid before. Of course, my spin on the receptiveness of these parents to something as ridiculous and dangerous as Geiers' Lupron protocol is that they are starting to realize that chelation therapy doesn't work, but that's a topic for another day. Ditto the disconnect between parents who are deeply suspicious of "conventional medicine" and "big pharma" who are willing to subject their precious children to powerful drugs that completely shut down the synthesis of sex hormones. A more "big pharma" overkill approach to autism I for one can't think of, but because it comes from the Geiers it's all too frequently accepted.
Kathleen's account is quite comprehensive; so I'm going to zero in on select aspects of it that I think I can elaborate on sufficiently to make it worth your while to read. One problem that using Lupron for an indication for which medical science does not support its use causes is due to the fact that it's an expensive drug. As one parent reported:
My son's Lupron Depot was $1538.00 pre shot, given every 30 days. Dr Geier did the shots on my son since my insurance would only cover them if they were done in a doctor's office. My Carefirst PPO did cover it but it was a real fight. (March 21, 2006)
Insurance companies often don't pay for "off-label" uses of drugs. They certainly don't pay for off-the-wall uses of drugs like the use of Lupron for autism. How will parents pay for this very expensive treatment protocol being administered by Dr. Geier? The Geiers appear to have the answer. They try to make a diagnosis of precocious puberty on these children. Unfortunately for this approach, precocious puberty is a pretty rare condition, as both Kathleen and I have discussed before, even having led me to ask: "Anyone want to take any bets on how long it is before there is a flood of autistic boys with the diagnosis of "precocious puberty?" (The answer, apparently, is "a few months.") The problem with this approach is that there are very specific diagnostic criteria for a diagnosis of precocious puberty, and among these are symptoms of the onset of secondary sexual characteristics before age 8 in girls and age 9 in boys coupled with increased bone age. In girls, that means the growth of breasts, wider hips, and the growth of pubic and underarm hair. In boys, it means the growth of facial, chest, underarm, and pubic hair; deepening of the voice; and enlargement of the penis and testes. In the absence of the premature onset of these secondary sexual characteristics, there is no real reason to do a workup for precocious puberty. Moreover, as mentioned before and as Kathleen emphasizes, precocious puberty is a rare condition:
Central precocious puberty (CPP) is the only pediatric condition for which sufficient evidence of safety and efficacy of Lupron exists to support FDA approval. With an estimated prevalence rate of 1:5,000 to 1:10,000 -- 90% of whom are female -- CPP is rare enough that a European endocrinological research consortium found it necessary to pool data from The Netherlands, Italy and France in order to accumulate 26 male subjects for a study of the effect of gonadotropin-releasing hormone agonist treatment on height.
Of course, none of this has stopped the Geiers from applying the diagnosis of CPP, medical appropriateness be damned, and if you ever ask one of these parents that inhabit the Evidence of Harm list who are supporters of the Lupron protocol to tell you the difference between CPP and peripheral precocious puberty (PPP), you'll generally get blank stares. Has anyone ever heard of confirmation bias? Basically, it's the human tendency to look for evidence that supports preexisting beliefs and to discount evidence that does not, all often on a subconcious level. Kathleen's account suggests that the Geiers, whether consciously or not, are using confirmation bias to their advantage by designing an interview guaranteed to plant the suggestion in parents that there are indeed signs of precocious puberty:
One year later, in his 2006 Autism One presentation, David Geier described a "novel" diagnostic interview in which parents were asked to report "signs of premature puberty" in their children, and offered examples of supposed behavioral and physical indicators of the condition: "This is an area that's very novel. We've now asked an awful lot of patients, and it's something that mainline physicians and other doctors aren't asking, which is, we asked for these patients, "do your children have signs of premature puberty?" And a fair number answered, "Yes." And then we start talking in our interview, asking for specific questions. And these are things that if your child is, say, under eleven or ten, if they are showing early sexual changes, meaning masturbation behaviors, they're showing aggressive behaviors, hair on their legs, mustache growing in, all of these things, growth spurt -- these are things that are not normal." (May 26, 2006)
Aggressive behaviors and self-stimulation are not necessarily abnormal in children under 9, and, in the absence of genital development and pubic hair, leg hair and growth spurts are not indicators of precocious puberty either. Worse, the Geiers are screening a series of over 30 lab values, looking for at least one that's abnormal. Kathleen didn't explain this (probably because she isn't a medical professional involved in clinical research), but if you screen for 30 lab values in almost anyone, you have a good chance of finding at least one that's abnormal. The reason for this is that "normal" for most laboratory values is defined as the range that encompasses 95% of the normal population without conditions that could be expected to change the lab value. Consequently, 5% of "normal" patients will have an abnormal value in any single lab test. If you screen for 20 lab values, there's a close to a 100% probability that one of the tests will be abnormal. Testing for 30 or more lab values, there's a pretty good chance that two or more of them will be abnormal. (Indeed, when peer reviewing papers, I have rejected papers that were guilty of looking at many variables without using statistics to control for multiple measured lab values or parameters for that very reason.) By using a "shotgun" workup, the Geiers almost guarantee that almost every child they test will fit into their diagnostic criteria. Whether this is simply because they do not understand how normal lab values are defined and the basic statistics that guarantee that testing large numbers of lab values will turn up at least one "abnormal" value that probably means nothing, I don't know. But Dr. Geier is a physician, and this is the sort of stuff I was taught in medical school when learning how to interpret panels of lab tests. I can't believe that Dr. Geier didn't also learn this in medical school himself, although diagnostic panels with multiple lab values in a single run were not as common back in the 1960's and 1970's. Or perhaps he's forgotten it. Another thing they taught me in medical school is that you don't treat lab values; you treat the patient. If the patient has no definitive physical signs of precocious puberty, there is no need to "treat" that patient for "precocious puberty" almost regardless of the lab values. Indeed, it is not even always necessary to treat children with a definitive diagnosis of CPP based on clinical signs, imaging studies, and lab values:
It is important to keep in mind that not all children with precocious puberty require treatment, especially if their bone age is not very advanced and they have a normal rate of growth. They will require frequent visits to their doctor to monitor their growth and development and to see if treatment is required at a later time.
Clearly, as Kathleen pointed out, all this testing seems as though it's designed to get insurance companies to pay for the Geiers' protocol to "lower testosterone" to make chelation therapy "work better," not to confirm a true diagnosis of CPP:
"Working with" a diagnosis of precocious puberty to justify prescriptions for Lupron administered in conjunction with chelation may serve to temporarily insulate Dr. Geier and Mr. Geier from criticism from "mainline medicine." A diagnostic interview in which parents are encouraged to regard common behaviors with a wide range of possible causes, such as aggression and masturbation, as indicative of a rare condition, may enable parents to be persuaded to consent to pharmaceutical treatment of their children for a nonexistent problem. A diagnostic process that is "not that restrictive" may enable parents of autistic children who might not meet criteria for CPP according to professional practice guidelines to "try out" Lupron on their children, and acquire the drug without incurring substantial out-of-pocket expenses; it may also facilitate recruitment of subjects for the Geiers' research, and minimize their costs in conducting it.
I have a real problem with that. The diagnosis of CPP is intentionally designed to be restrictive, because there's a fairly wide range of normal ages for children to begin to enter puberty and because the treatment for CPP is not benign. As evidence of the Geiers "not that restrictive" criteria for the diagnosis of CPP, Kathleen presents examples in which parents are urged not to tell their insurance companies that their child is also undergoing chelation therapy, presumably because that would be a red flag. Even worse, she describes examples of the diagnosis of CPP being given to children 9 or older who by definition can't have CPP--period.
Going through Kathleen's report, I have to congratulate her on how well-documented, detailed, and comprehensive her takedown of the Geiers is. If there were a Pulitzer Prize for blogging, she should be nominated for it. Three times now, she has exposed the dubious "research" practices of Mark and David Geier. In each new installment, the story gets worse than what was described in the installment before. At the end of this third installment, Kathleen finishes, as she has with the previous installments, with a big "to be continued."
That promise makes me afraid of what I'll read when next she posts.
Orac, thanks for posting that. Knowing the mechanism of Lupron's action and its appropriate usage, one can only conclude that this guy is batshit crazy.
Crazy yes, byt very brilliantly crazy. A great many parents -- particularly the religious ones -- are scared at the thought of their children entering puberty to begin with, and as many are more used to thinking of it happening in the early teens, and aren't aware of the precipitous drop in the average age which it is beginning these days. So if they hear that a drug will both 'cure' their child's 'autism' AND delay puberty, this will be looked on as a PLUS. Poor kids.
One thing I am curious about. What specifically is the problem with 'precocious puberty'? Is it the sudden growth spurt, or some hormonal imbalance, or what?
How Does Precocious Puberty Affect a Child?
When puberty ends, growth in height stops. Because their skeletons mature and bone growth stops at an earlier age than normal, kids with precocious puberty usually don't achieve their full adult height potential. Their early growth spurt may make them initially tall when compared with their peers, but they may stop growing too soon and end up at a shorter height than they would have otherwise.
Going through puberty early can also be difficult for a child emotionally and socially. For example, girls with precocious puberty may be confused or embarrassed about physical changes such as getting their periods or having enlarged breasts well before any of their peers. But the hardest part may be the teasing that children with the condition - especially girls - may experience.
Even emotions and behavior may change in children with precocious puberty. Girls can become moody and irritable. Boys can become more aggressive and also develop a sex drive inappropriate for their age.
The growth spurt is actually quite impressive (my daughter did 3 inches in less than 3 months last fall), however, if this happens in a child of average height at age 7 or 8 (average hight at that age is around 130 cms/4"4'), the child might very well end up under 150 cms/5".
Is there any actual way to stop these quacks?
Actually, if they really are making bogus diagnoses for the purpose of getting insurance companies to pay to give dangerous drugs to kids that don't need it, this is both fraud and medical malpractice.
Someone needs to bring this to the attention of both the medical boards and the insurance companies. Especially the insurance companies - they don't like to be defrauded, not one bit. And they've got the influence to get something done about it.
"A great many parents -- particularly the religious ones -- are scared at the thought of their children entering puberty..."
Huh? I think lunacy has no particular religion. Let's not jump to think just because someone ascribes to a particular faith that they're somehow better suited to buy into this load of dung from the Geiers. I'd be inclined to say the exact opposite...I find that the anti-vax parents I know are parents who have little or no religious affiliation and have no other outlet for their "faith" so they turn to people like the Geriers looking for a miracle.
Thanks Orac for another great summary and commentary to Kathleen's work.
I have a relatively minor quibble with your multiple comparisons argument.
Consequently, 5% of "normal" patients will have an abnormal value in any single lab test. If you screen for 20 lab values, there's a close to a 100% probability that one of the tests will be abnormal.
I get something a little different. If you assume independence among lab tests (an admittedly poor assumption that I'll return to in a moment) then the probability of a "normal" patient having no abnormal test results is 0.9520 approx.= 0.36. So the probability of at least one abnormal test in these conditions is approx. 0.64.
Correlations among the tests should increase the probability of no abnormal test results (assuming, again, the patient is "normal"), and so should decrease the probability of having at least one abnormal one.
For 30 patients, the probability of 0 or 1 abnormal test result under independence is 0.9530 + 30 * 0.9529 * 0.05 approx.= 0.55, so the probability of having at least 2 abnormal results is approx. 0.45.
So while your point about the Geier protocol casting too wide a net is well taken, I can't quite agree with the statement that the lab test would allow essentially anybody into the protocol.
You mentioned that the elder Geier is a physician...I'm sure you've mentioned it before, but what is his subspecialty? The reason I ask is because if he's affiliated with his specialty's organization (ie American Academy of Pediatrics), it might be possible to work through them to try to stop him. The IRB issue alone ought to be enough to convince them to do something.
Also, I wonder if the major medical insurance companies would simply stop accepting any claims from Dr. Geier if they knew that he was committing insurance fraud?
You'll forgive me. It was late when I wrote this and, rather than actually sitting down and doing the calculations, I just eyeballed it. In any case, your analysis does not invalidate my point. The expected rate of CPP is between 1:5,000 and 1:10,000, considerably less among boys, who make up 80% of autistic children. If the Geiers cast a net that has, for the sake of argument, a 50% chance of labeling a child as having precocious puberty, when the real chance is several orders of magnitude less than that (even if you accept that the risk may be somewhat higher in autistic children), you see that virtually all the diagnoses the Geiers make are false positives. Actually, they're not even false positives, because the Geiers didn't bother to do many of the actual required tests and because they use diagnostic criteria that are not correct. So basically, whether 50% or close to 100% of "normals" will turn up at least one abnormal lab value using the Geiers' methodology is a distinction without a real difference.
Also, although your point about correlations between lab values is well-taken, do you really think that the Geiers look at these 30+ lab values and check for expected groups of lab values being abnormal in the pattern expected, using that information to throw out spurious lab values or as a reason to recheck individual abnormal labs? I don't. According to Kathleen's article, Dr. Geier himself has said that they only need one abnormality to justify using their protocol.
I'm posting this one anonymously (although Orac will figure out who I am) because of my job. I work for an insurance company, and have done reviews for fraudulent activity. Unfortunately, unless someone is honest enough to "spill the beans" about the member/provider fraud to the insurance company, insurance fraud in this manner is rather easy. Our medical policies, which are reviewed annually to keep up with changes in evidence-based medicine, state that Lupron requires medical review and authorization for the diagnosis of true or central precocious puberty. If you submit physician records that meet our criteria for the diagnosis, the treatment will be approved. We accept medical records as true UNTIL proven otherwise and the Geiers seem to be aware of this. (However, thanks to Orac and Kathleen's blogs, our medical policy department is aware of this horrible usage of a strong medication and is watching out for instances of its occurance.)
For policies that have drug plans which will cover Lupron for CPP or members whose plans don't require authorization, it's very difficult to find the fraudulent activity IF you don't know what you are looking for. It's rather like looking for a needle in a haystack.
If we find fraud...that's an entirely different story....
Why, damn you, too, honey!
Seriously, Orac, thanks again and again for helping to provoke some outrage about this, and for adding depth to the story with your clinician's perspective. Fair warning: I am far from finished with this series.
Prup, you make a good point about how some parents might regard artificial postponement of puberty as a good thing. Almost by definition, a pubescent autistic child's social skills aren't going to be up to the same speed as their hormones. Difficult situations are par for the course, and can result in serious consequences. It's completely reasonable for parents to experience anxiety surrounding their ASD children's sexual development. But it wouldn't be reasonable to deliberately interfere with it.
And Anon, you have made my day. I've been so busy researching and writing the articles that I haven't yet had a chance to write to all of the people who might be able to do something to stop this. I'm guessing that there's only so much the FDA would be able to do, since it's legal to prescribe drugs for off-label use. (Orac, please correct me if I'm wrong.) OHRP could eventually rescind the IRB registration, but they're a federal agency, and you know how slowly those tend to move. State Attorneys General might take time to motivate, especially if enforcement budgets are thin. Maryland would be a starter, then other states, because Dr. Geier reportedly offers long-distance telephone consultations, and various DAN! doctors (such as Dr. Mary Megson of Virginia) have reportedly cooperated with him.
But insurance companies should want to plug the hole in the dike just as soon as they wake up to the fact that thousands and thousands of dollars gushing through it. And THAT is what will stop the flow of Lupron into autistic kids.
I would suggest getting some *real* experts on the case, professionals who know their endocrinology and would be even more outraged than we are - PubMed identifies great candidates, like this one:
According to the Maryland Board of Physicians, Dr. Mark Geier's license is set to expire on Sept. 30, 2006. Since I presume this means he will need to reapply for his license soon, now might be as good a time as any file a complaint
(type in "Geier" to do a search for him)
Maryland Board of Physicians:
Under Maryland General Health Occupations law (gho) section 14-404(a): "Subject to the hearing provisions of Â§ 14-405 of this subtitle, the Board, on the affirmative vote of a majority of the quorum, may reprimand any licensee, place any licensee on probation, or suspend or revoke a license if the licensee:...
(11) Willfully makes or files a false report or record in the practice of medicine;"
It is possible that the diagnosis of CPP in a patient whose age makes such a diagnosis physically impossible would fall under this statute.
also in 14-404(a):
(17)Makes a willful misrepresentation in treatment;
(18)Practices medicine with an unauthorized person or aids an unauthorized person in the practice of medicine;
(22)Fails to meet appropriate standards as determined by appropriate peer review for the delivery of quality medical and surgical care performed in an outpatient surgical facility, office, hospital, or any other location in this State;
(27)Sells, prescribes, gives away, or administers drugs for illegal or illegitimate medical purposes;
It is possible that Dr. Geier has violated one or more of the above regulations. If enough evidence can be gathered to present to the State Board of Physicians to show violation, then at the very least a cease and desist order could be obtained.
Orac, you said:
You'll forgive me. It was late when I wrote this and, rather than actually sitting down and doing the calculations, I just eyeballed it. In any case, your analysis does not invalidate my point.
to which I'll repeat:
I have a relatively minor quibble with your multiple comparisons argument.
I don't disagree with your core argument, that they cast a far too wide a net in recruiting.
In fact, I've been following Kathleen's series, and I'm deeply disturbed by the Geier's activity surrounding the Lupron protocol, especially when there are legitimate mechanisms for extending the label of a drug (which, granted, are more difficult than simply writing up a protocol and submitting it to an IRB for which you are the chair).
Even in the unlikely event that their testosterone hypothesis is correct, their actions still constitute fraud and still should be investigated under the Office of Research Integrity.
Kathleen, I assume you've gone here? http://ori.hhs.gov/education/products/rcr_humans.shtml
About Dr. Grier loosing his license: Do you think it likely he would or that the fuss about it would just fuel the conspiracy of "big pharma is out to get me?"
Conspiracy theories are designed to feed off of anything.
I often wonder, in all this lovely debate, if the Geiers actually "think" about how the children feel. As one autistic adult has said, "The next time you think of autistic children, remember that children grow up."
Can you imagine the horror of being subjected to all kinds of crazy treatments, only to grow up and be scarred with the fact that your parents are always looking for treatments because you're "abnormal, deficient, weird, crazy, and now...completely off on your normal growth cycle?" I've heard from Downs Syndrome parents that there's something really special about their kids. Couldn't we leave these kids alone, and start boosting their positive aspects, instead of trying to cure all their deficits? These kids don't even sound human after the Geiers get done with them!