Vaccines, Autism, Science, and Special Pleading
October 25, 2008 by Do'C 
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As noted by Kristina, over at AutismVox, Newsweek has three interesting video interviews on the subject of vaccines and autism. There are interviews with Paul Offit, MD, Robert Krakow, Esq., and Kristina Chew, PhD.
On Newsweek: Three videos with interviews with Dr. Paul Offit, chief of the division of infectious diseases at the Children’s Hospital of Philadelphia and a professor of pediatrics at the University of Pennsylvania medical school; Robert Krakow, a New York attorney who’s the father of an autistic son and who is representing more than 75 families who believe a vaccine caused autism in their child; and myself. The videos are below or go here to Newsweek.—— And here’s a profile of Dr. Offit by Claudia Kalb in Newsweek.
Note: All three videos (in their entirety) are currently available at Newsweek, attached to the story about reaction to Senator McCains recent debate comments about special needs families, or embedded in the blog post over at AutismVox.
In light of Dr. Offit’s statement [about whether or not vaccines cause autism] that, “It’s a scientific question,” I found part of Bob Krakow’s interview quite interesting. I found it interesting because Bob Krakow himself has apparently expressed understanding of the fact that the question is a scientific one, in the not too distant past.
Addendum (10/26/2008)
If the embedded video is not working, you may be able to view it here.
Original videos at Newsweek.com (see “Featured Videos” section)
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Comment by HCN — 25 October, 2008 @ 9:55 pm
The plural of anecdote is not data.
Still, are people still convicted for murder by stories/anecdote ? Doesn’t there have to be other corroborating evidence? Like physical evidence, or testimony (anecdote) from more than one person?
Anyway, isn’t science supposed to work differently than law?
Comment by Do'C — 25 October, 2008 @ 10:03 pm
I’m sure in murder cases, more is required, and Krakow comments on that in the video. However, it’s still not relevant to answering a scientific question.
Comment by Joseph — 26 October, 2008 @ 7:48 am
I think you also need to have motive, means and opportunity.
But the analogy doesn’t work in other ways.
If a witness claims to have seen a murder being committed, there are only a couple possibilities: (1) The witness saw a murder being committed, or (2) The witness is lying under oath.
If a parent claims that their child regressed after vaccination, there are a number of possibilities: (1) The child actually regressed because of vaccines; (2) The child regressed because of some other cause that occurred at about the same time; (3) The parent has recall bias in regards to the timing of vaccination (demonstrated scientifically); (4) The parent’s subjective evaluation of child development is biased (Cedillo case); (5) The parent is lying because they think they can obtain financial security for their disabled child by suing the government; etc.
Comment by MC — 26 October, 2008 @ 7:49 am
If people have been convicted of murder with the level of evidence for the autism/vaccine idea, we owe a lot of people new trials and should put a halt on all capital punishment until every case can be reviewed.
Comment by Robert Krakow — 26 October, 2008 @ 9:21 am
Dear Autism Street:
I anticipated that there would be comments like the one you made and those made in one of the comments you have published. Thank you for the opportunity to respond.
You need to understand that this was an hour or more long interview edited down to a couple of minutes.
I stand by my statement about anecdotal evidence being valid evidence. A murderer can be convicted by purely circumstantial evidence, call it anecdotal or some similar type of description.
There is no doubt that corroborating evidence makes the case stronger. In the part of the interview edited out I describe some of that evidence, although for the most part a detailed explication of the scientific support for the proposition that vaccines cause autism was beyond the scope of the interview.
My only point is that parents’ observations of what happened to their kids should not be dismissed. Anecdotal accounts of what happened to their children are valid and should be considered. And, if you listen carefully to what I said, other evidence must be produced to support credible anecdotal evidence. I strongly believe that such evidence is available and that more will be produced.
There is also no doubt, as I explained in the interview that neither the IOM (p. 61 of May 18, 2004 IOM report) nor leading epidemiologists have ruled out that vaccines may have injured a susceptible subset of children. See Verstraeten’s letter to Pediatrics (stating categorically that the CDC study of the VSD data that he coauthored did not disprove a vaccine/thimerosal causal link to autism and NDD’s), Bernadine Healy’s public statements on the suppression of inquiry into the vaccine-autism link, and the testimony of Sander Greenland, Ph.D. at the recent thimerosal test case in vaccine court. (pp. 69-119 of transcript of May 12, 2008 in King and Mead cases).
Credibility is always a factor, and parent accounts can easily be corroborated by other reports, including medical records and other witness accounts.
Please also understand that in vaccine court and other judicial venues “challenge”, “positive rechallenge” evidence is accepted as proof of causation. Adverse outcomes temporally proximate to vaccine administration is highly probative on the issue of whether vaccines caused the adverse outcome.
I hope this helps to clarify my comments and the issues on which you commented.
Thank you.
Robert J. Krakow, Esq.
Comment by MC — 26 October, 2008 @ 10:15 am
I appreciate Mr Krakow taking the time to respond.
However, I would suggest that he is leaving out a few very important points still.
1) The argument for a very long time–one still held by many–is not that there is a small susceptible group. Rather the argument has been that there is an “epidemic” of vaccine-induced autism.
2) the biologic plausibility arguments are rather thin.
3) Corroborating a parent’s view has been shown to be difficult. Case in point, Cedillo. Parental observation was shown to have clearly missed earlier signs of autism. There is another case, of which you are no doubt very familiar, where the expert report indicates loss of skills before the flu vaccines indicated as the causal factor in a regression.
4) Corroborating parental reports can go to timing, not to demonstrating a plausible argument can be made for causality.
To abuse your own analogy–you might be able to put the suspect in the right place at the right time. But if the evidence is that the suspect was unarmed, how do you make the case for a murder conviction?
Comment by Joseph — 26 October, 2008 @ 10:35 am
Does anecdotal evidence have zero value? Of course not. But I think it’s also important not to give it more value than it has, and to consider it in the context of other knowledge (such as the knowledge of outcomes in autism as reported historically, or the knowledge about recall bias).
An interesting post on the limitations and the role of anecdotes as medical evidence is the following, by Steve Novella:
http://www.sciencebasedmedicine.org/?p=33
Comment by Do'C — 26 October, 2008 @ 10:48 am
Hi Mr. Krakow, thank you for stopping by and commenting, it is appreciated.
Noted.
The question of whether or not vaccines can cause autism is a scientific one. Abandoning the presentation of any detailed scientfic explanation due to the limited scope of the interview is certainly understandable (and not an enviable position), but it doesn’t address that scientific question. Introducing a non-scientific standard for acceptance of evidence for the answer to a scientific question is special pleading.
I agree. Parental observations should not be dismissed in general, they’re a key component of the hypothesis and should be carefully considered, but they are not scientific evidence for the truth (or lack thereof) of a scientific hypothesis.
The scientific question of whether or not vaccines can cause autism, can never be answered with 100% certainty in favor of “not” by real scientists. Possibility (however infinitely small) always exists. Many people don’t do well with such uncertainty. However, the truth of the answer to a scientific question requires scientific evidence of its truth. For those making the claim that vaccines can cause autism, the burden of proof is for those making the claim to prove that they do, not others to prove that they don’t.
While not necessarily relevant to autism, these can make sense from a procedural perspective. I’m not sure what they have to do with answering the scientific question, “Can vaccines cause autism?”. While anecdotes may help form the scientific question, they certainly don’t answer it - which is what you appeared to be pleading for.
Comment by Prometheus — 26 October, 2008 @ 11:12 am
Mr. Krakow (esq.) seems to be determined to undermine my faith in the justice system.
If people are convicted of crimes and sent to prison on “anecdotal evidence” of the same quality as that supporting the “vaccine-cause-autism” hypothesis, then we should not only suspend executions, we should consider firing all the prosecutors, judges and defense attorneys and starting over from scratch.
Let me try an analogy.
If Mike were accused of murdering Frank, the “evidence” - were it of the same caliber as the “vaccines-cause-autism” “data” - would be as follows:
[1] Mike bumped into Frank on the street.
[2] Some time later - maybe a day, maybe a week, maybe three months - Frank was found dead.
[3] The coroner’s report said that Frank died of unknown causes. No injuries were found on Frank’s body that could be traced back to Mike.
[4] The prosecutor showed that people like Mike (white, male, between 20 and 30 years old) have killed people in the past - although none of their victims had shown the same pattern of injuries (or lack of injuries) as was found on Frank.
So, Mr. Krakow (esq.) is telling me that he would prosecute - and possibly convict - someone of murder with the same quality of evidence that he finds so compelling in the “vaccines-cause-autism” story.
Mr. Krakow (esq.) also seems to be inadvertently making the point that only a very small number of autistic children are made that way by vaccines.
He appears to agree that while vaccines cannot be completely exonerated by the present epidemiological data, the number of children made autistic by vaccines is - at most - a very small percentage. According to the IOM and Dr. Verstraeten, the number of children whose autism was caused by vaccines is somewhere between “very few” and “none”. That’s what the data show.
I call on Mr. Krakow (esq.) to help resolve this dilemma. If he is saying that we should accept the parents’ “stories” as data, shouldn’t we also accept the data as data?
And if we’re going to accept the parents’ “stories” as data, shouldn’t we make an effort to find out all the stories? Or, at least, shouldn’t we try to get a representative sample of those stories?
What about all the parents whose children became autistic without vaccines? Those stories exist, even if Mr. Krakow (esq.) doesn’t want to acknowledge them. Those “stories” not only support the current consensus that vaccines aren’t a significant factor in autism, they also show that the “stories” of how children became autistic after vaccines are most probably a matter of coincidence rather than causation.
Let me help Mr. Krakow (esq.) to understand this:
If you were trying to convict someone - Mike, for instance - of a series of identical murders and you found that several of those murders had occured while Mike was in prison, wouldn’t that effectively demolish your case against Mike?
Connect the dots, Mr. Krakow (esq.).
Finally, if vaccines (or the “toxins” therein) cause - at most - only a small fraction of the cases of autism we see today, what does that say about the “epidemic” of autism?
Mr. Krakow (esq.) is apparently trying to have his cake and eat it, too. He wants to have vaccines be a (the?) cause of autism, but he wants to ignore the data showing that vaccines could cause - at most - only a small fraction of the autism we see today.
If vaccines aren’t a significant cause of autism, then what is causing the “autism epidemic”?
Perhaps it is the explosion of tort lawyers in the Western world. Or maybe it’s cell phone use. Or Prius emissions. Or the “tsunami” of clueless celebrities spouting uninformed opinions on television.
Whatever it is, it’s not vaccines.
Prometheus
Comment by Melody — 26 October, 2008 @ 11:57 am
And, supposing even if a small minority of autistic children became autistic because of vaccines (which I don’t think so because of the lack of biologic plausibility, but who knows, somebody may present some plausible theory someday), that’s no reason to rail against vaccines like they are evil, which would scare people off of the vaccine and result in increases of preventable diseases (and practically zero change in autism rate).
The life-saving potential of vaccines is far greater than the potential for adverse reactions, whether you include autism in the latter or not.
Comment by alyric — 26 October, 2008 @ 3:58 pm
Mr Krakow wrote:
“There is also no doubt, as I explained in the interview that neither the IOM (p. 61 of May 18, 2004 IOM report) nor leading epidemiologists have ruled out that vaccines may have injured a susceptible subset of children. See Verstraeten’s letter to Pediatrics (stating categorically that the CDC study of the VSD data that he coauthored did not disprove a vaccine/thimerosal causal link to autism and NDD’s), Bernadine Healy’s public statements on the suppression of inquiry into the vaccine-autism link, and the testimony of Sander Greenland, Ph.D. at the recent thimerosal test case in vaccine court. (pp. 69-119 of transcript of May 12, 2008 in King and Mead cases).”
Not a good idea to forget for a moment that Mr Krakow is collecting 75 sets of fees in the Omnibus, so whether or not he believes any of what he wrote is something of an interesting question, not to say an ethical question mark of considerable interest but more on that later.
The points he raises are three and I recall one from the interview.
1. Verstraeten posted a correlation at first. True and Geier, pere et fils found it good enought to plagiarise. However, this first ecological look at hte data raise a large number of questions - notably, how to check if the data was correct, which the subsequent and individual level study checked most thoroughly and lo and behold, no correlation to any kind of neurological problem. My, but this demonstrates the superiority of individual level studsies over ecological ones with this sort of data. Now, why does Mr Krakow take the first study and ignore the second, which is superior?
2. There is s subset of children who may be affected and standard epidemiology misses that subset. Well, no actually. I was so glad to see this so unequivocally stated by Offit - epidemio;ogical studies are more than capable of picking up even tiny subsets of possibly affected individuals - down to 1:100, 000. So, is Mr Krakow talking about a subset of around 1 in a thousand of those currently diagnosed ASD? I didn;t think so since that would demolish the Omnibus - for lack of cases.
3. Bernadine Healy. Ah yes and I’ll bet she regrets every syllable of that silly statement. Olmsted tried to get her to a) acknowledge it and b) expand on it. No such luck, the lady remained coy and umcommunicative, which would be no surprise to those unlucky enough to have worked for her in the past. Healy is there for Healy and this should have been a nice safe politically correct statement, except that it wasn’t. And the reason is that even a self-serving beaurocrat like Healy has to back up what she says or implies and of course she could not.
3. Sander Greenland’s testimony, which I don’t recall. But, was there any testimony on behalf of the parents that wasn’t thoroughly demolished? If Greenland’s stood up, it was the only one that did. Must go and read the transcript.
4. Krakow refers to ‘other papers; that find a link between vaccines and ASD’s, which can only refer to the Geiers. Wasn’t it nice of the special master to make it quite clear that people should not be asking the Geiers for expertise and anyway, the VCIP would find a way not to pay for most of it if they did. Kathleen Seidel’s latest is a must read.
Now to Krakow and the ethical dilemma. Sorry to put a ding in your faith in the course of Lady Justice Prometheus, but…..
Krakow may or may not believe in the case he upholds on behalf of parents. He certainly doesn’t have to. The only absolute requirement is that the parents believe it and continue the litigation course. No parents = no fees. For those who keep an eye on the Yahoo group evidence of harm it’s a bit interesti ng to see who are the true believers and who only have a vested interest in keeping the litigation boat afloat. Krakow and a few other inmates - Aasa, Theresa Binstock, one or two others have this deft knack of shoring up the cracks of uncertainty should any evidence that there are holes in the autism = vaccine damage hypothesis arise. There might be a case of SIDS or HPV supposedly gone wrong. Whatever chivvies the worried back into the true belever status is what comes up. Oddly Schafer is not one of the herders - he’s a true believer though much less than he used to be.
Comment by HCN — 26 October, 2008 @ 6:28 pm
alyric said “Verstraeten posted a correlation at first. … However, this first ecological look at hte data raise a large number of questions - notably, how to check if the data was correct, which the subsequent and individual level study checked most thoroughly and lo and behold, no correlation to any kind of neurological problem. …..Now, why does Mr Krakow take the first study and ignore the second, which is superior?”
There is a very good explanation of the criticisms of the first study in Dr. Offit’s book “Autism’s False Prophets” starting on page 92. Mr. Krakow would do well to look at the issues brought up by Dr. Stehr-Green and Dr. Davis.
Now about evidence in a murder trial versus that of vaccines in autism. Since the finger pointing at vaccines is because autism is usually diagnosed at about the time some vaccines are given. This was not an issue I encountered since my son’s seizures started before he had any vaccines (as a two-day old newborn), and his very severe speech delay was remarked on during the time his brother was being born (the doctor’s wife was also having a baby on that day in that hospital, and his two year old daughter was talking up a storm)… so my son’s speech issue was discussed before any two year old vaccines in the hospital’s birthing center (his brother is four days short of being two years younger).
It is like the suspect in a murder being the person who was there when the murder is discovered by others. Like a person who came upon the dying victim is being blamed, even though they have no weapon… much like this LOLcat scenario (caution, humor ahead):
http://icanhascheezburger.com/2008/10/26/funny-pictures-im-telling-you-he-was-dead/
Comment by Robert Krakow — 27 October, 2008 @ 12:09 pm
Dear bloggers:
I find it amusing that some of you have cherry-picked my comments in an edited video, that was further spliced for this blog, and then served up prone for criticism. Such techniques are hardly fair, but have become acceptable in blogland. Some of your commenters like to establish false straw men, then triumphantly knock them down. I prefer more sober and intellectually honest debate when it comes to the welfare of injured children.
I did not analogize the claim “against vaccines” to prosecution of a murderer. My point, perhaps diluted due to editing, is that certain kinds of evidence, in this case first person parental accounts, also described as “anecdotal evidence”, is valid. I stated very carefully that the process of evaluating such evidence requires an assessment of credibility and the production of corroborating proof, in this case science. The disparaging of parental accounts as “merely” anecdotal” is a way of dismissing the credibility of parents. My point is that even in a matters as important as a murder prosecution “anecdotal evidence” or its equivalent is acceptable as proof.
I did not suggest in the interview nor would I ever argue that scientific proof is unnecessary for a claim that vaccines caused neurodevelopmental disorders, generally or in a specific case. I believe there is ample proof of the connection supported by credible researchers, and medical experts, notwithstanding the suppression of this area of research.
By the way, I had no knowledge that Newsweek’s story was about Dr. Offit, so placing my interview after his, suggesting I am at “odds” with him (which I am) is not really appropriate when my interview focused on subjects other than Dr. Offit or his views.
Sincerely,
Bob Krakow
Comment by Do'C — 27 October, 2008 @ 8:15 pm
Hi Mr. Krakow, you are right, the comment that caught my interest from the Newsweek video was singled out. I can certainly understand why you may not like criticism, but I’m not sure why you may think it so unfair. I included links to the complete (Newsweek-edited) video in several places, and your counterpoints to any criticism are welcome. If you have a logical argument to make, it will surely stand up to minor criticism in the long run.
Claiming ownership of moral high ground with respect to children’s welfare?
Your point is noted. My point is that this kind of evidence usefully serves to formulate a scientific question, not answer one.
Hogwash. This can really only be seen as true if one considers parental accounts valid in answering a scientific question in the first place - and then the special pleading stands. The credibility of parental accounts in formulating the scientific question in the first place is irrelevant to answering that scientific question. Allow me to provide an example that may have less emotional attachment for you. Joe Parent may have, or lack, all the credibility in the world. Joe Parent claims that his child went from non-verbal to verbal after a few weeks of giving homeopathic “remedies”. Science can address the question of whether or not the homeopathic “remedies” were likely to have anything to do with the acquisition of speech for the child. Is Joe Parent’s credibility relevant to that science?
It’s pretty obvious you may be unable or unwilling to acknowledge that the question of whether or not vaccines can cause autism is a scientific one. Anecdotes are not acceptable as scientific proof, and to suggest otherwise is special pleading.
It seems that this is exactly what you are implying. If you consider scientific proof necessary, then why on earth would you consider anecdotes necessary or even relevant? The anecdotes have been noted. They helped form the scientific question in the first place, remember? If you consider scientific proof necessary to answer the question, anecdotes are rendered moot in a reality-based world.
Can you explain, in your own words, which few pieces of reasearch you find the most compelling and why?
The story was about a mother’s response to Sarah Palin and John McCain. Have I posted an incorrect link somewhere?
Comment by Prometheus — 28 October, 2008 @ 12:59 am
Mr. Krakow complains that:
Describing parental accounts as “anecdotal” or even “merely anecdotal” is not disparaging in the least - it is an accurate description of them. It also says nothing about the credibility of the parents.
A parent’s account of their child’s illness is an anecdote. A police officer’s description of the events of a crime is an anecdote. That is an accurate description of what they are. If I thought they were unreliable or untruthful, I would preface the term “anecdote” with the adjectives “unreliable” or “untruthful”.
In science, anecdotes are a form of data, albeit of the lowest quality. A series of consistent anecdotes can be used to construct a hypothesis, which can then be tested by experimental means.
Although anecdotes can occasionally be helpful in pointing the direction to start, they are equally likely to point in the wrong direction. This is because anecdotes are informal observations that are performed in an uncontrolled environment (and often not recorded until well after the fact).
No matter how many anecdotes you accumulate, they can never “trump” real data. In Mr. Krakow’s legal world, even a busload of eyewitnesses claiming that they saw the defendent commit a crime cannot “trump” hard evidence that he didn’t do it.
Mr. Krakow goes on to say:
I suspect that Mr. Krakow is aware of the difference between a factual account of the events of a case - legal or medical - and rendering an opinion about how or why an event occurred.
It is one thing to accept at face value the parents’ account of what happened and when - although recent cases in the Autism Omnibus Proceedings have shown - once again - just how unreliable the human mind is at ordering and recalling events.
It is an entirely different matter to accept as factual the parents’ opinion(s) about what caused their child’s autism.
This is the “special pleading” that Mr. Krakow is trying to sneak in under the guise of “believing the parents”.
I have no problem accepting - within reason - the parents’ accounts of what happened and when (taking into account what is known about the reliability of human memory). Even that is still “merely an anecdote”, to be relied on only if it doesn’t conflict with better data.
What Mr. Krakow wants us to “believe” is the parents’ opinions about what caused their children’s autism. Even in court, a parent’s uninformed opinion would not be accepted as evidence - as Mr. Krakow knows all too well.
Science is even more strict than a court of law. Opinion, even “expert opinion”, won’t get you anywhere. You have to have data - not anecdotes.
The reason for this is simple: centuries of bitter experience have shown that the best way to keep from fooling ourselves into seeing what we want to see is to follow the scientific method. It may not be pretty and it may not stroke many egos, but it has about two centuries of success behind it.
From the scientific perspective, most of the more popular XYZ-causes-autism “stories” are barely into the hypothesis-forming state. Some of them - such as the now-defunct thimerosal-causes-autism idea - had barely formed a testable hypothesis before they were brutally gunned down by data. This is because the people making the hypotheses rarely bother to go any further.
The “alternative” autism therapy “world” is littered with poorly-formed, untested hypotheses that are treated as established fact. This is one of the reasons that their “experts” keep getting blown out of court. Most of the time, they don’t even have a hypothesis - they just have an idea of how things might have happened.
Here’s a suggestion for Mr. Krakow:
Take the parental anecdotes and form them into a testable hypothesis (or have someone do that for you). Then, do the experiments that will test the hypothesis. Using the data from those experiments, refine your hypothesis (”refine” often means the same thing as “tear it up and start over”) and test it in a different way. Then you might actually learn something about autism.
All of the “wins” in court, “wins” in the legislature and “wins” in public opinion will mean nothing if the hypothesis (or idea) that “wins” in these ways is wrong.
If thimerosal, vaccines and aluminium don’t actually cause autism, getting a court or Congress to say they do will only set back autism research.
Think about the possible consequences if you’re wrong, Mr. Krakow - no matter how unlikely you think that might be. You won’t change the outcome of the science by “pushing” a wrong idea, but you just might slow down the pace of discovery.
Prometheus
Comment by passionlessDrone — 28 October, 2008 @ 9:34 am
Hello friends -
As opposed to worrying about if the parents conclusions about vaccines ‘causing’ autism are valid evidence or not, perhaps we should take another tact at understanding the feasibility of what they claim to have observed.
One way to do this might be to ask, ‘Do we have evidence that a child with autism will react differently to a vaccine than a child without autism?’
It turns out, we do have some emerging research that points in exactly this direction.
“Macrophage migration inhibitory factor and autism spectrum disorders”
Link
Of particular importance here is that this chemical is known to overexpress the toll like receptors; which are the heart and soul of how vaccination (or any immune response) actually works. As levels of this factor increases, so do measures of autism severity. This, it would seem, would be logical evidence that in some children with autism would react differentially to vaccination than their undiagosed peers. This, of course, wouldn’t mean that the vaccine ’caused’ their autism; but it would be evidence that observations of seemingly abnormal responses to vaccines are not necessarily fabricated or the result of poor memories. There is a biological mechanism of action that is different in some children with autism that is tied to the triggering of an immune response.
Increased levels of this chemical have also been identified in several other auto immune related disorders with unexplainable increases such as asthma, type 1 diabetes, and juvenile arthrititis.
We also have clinical analysis that tells us that some children with autism create cytokines at different levels when their toll like receptors are triggered via agonists.
Evaluation of atopy and immune functions in children with autism spectrum disorders (ASD): Identification of an ASD subset with distinct clinical and immunological findings
Link
Again, not proof of causation, far from it, but good evidence of abnormalities in the immune system actively triggered by vaccines do exist in a subset of children with autism.
OK!
- pD
Comment by María Luján — 28 October, 2008 @ 2:39 pm
Anecdotes are being more and more studied…especially considering adverse effects of medications
RANDOMIZED, CONTROLLED TRIALS, OBSERVATIONAL STUDIES, AND THE HIERARCHY OF RESEARCH DESIGNS
Link
Comment by María Luján — 28 October, 2008 @ 3:29 pm
More…
Adverse drug reactions – no farewell to harms
Jeffrey K Aronson, Editor-in-Chief, British Journal of Clinical Pharmacology
Link
It is certainly the case that some adverse drug reactions appear not to be related to the dose or concentration in the therapeutic range of doses. There are two possible reasons for this. The first reason is that the relation between the dose, which is relatively easily determined, and the concentration at the site of action, which is not, is highly variable, and an absence of a dose–effect relation does not necessarily imply an absence of a concentration–effect relation; this may occasionally explain apparent non-dose-relatedness. The second, and more important, reason is that effects that appear not to be dose-related are saturated in the therapeutic range but are dose-related in the range of doses below the therapeutic range; in other words, they are hypersusceptibility reactions
The factors that increase an individual’s susceptibility to an adverse effect can be remembered from the mnemonic GASPED – genetic, age-related, sex-related, physiological (e.g. pregnancy), exogenous (e.g. drugs, food), and disease-related.
Anecdotes that provide definitive evidence
When a criminal is caught in the act, other evidence is unnecessary. Should the same be true for adverse drug reactions?
Comment by Do'C — 28 October, 2008 @ 7:37 pm
María,
The first citation you provided is not about anecdotes at all.
It is a look at randomized, controlled studies and relative utility of well-designed, cohort or case–control observational studies in conjuction with randomized, controlled studies.
Hopefully, you caught this point from the authors as well:
Well-designed cohort or case–control observational studies may not be equivalent to a randomized, controlled study, but they are not anecdotes.
Your second excerpt from the editorial is interesting, but the points that better discuss anecdotes are a few paragraphs after the piece you excerpted. Here’s an interesting piece:
The third link is interesting too, especially if one reads this entire commentary. Pay very close attention to the specific definitive adverse events of drug reactions. If you’re inclined to think that “specific anatomical location or pattern of injury” applies to autism, I suggest a look a table 1 and additional reading on the subject.
María, your points are noted. I’m not sure how relevant they are in the context of the current discussion (autism) and parental reports, but the subject is interesting.
Thank you for posting links instead of entire studies that may not be relevant.
Comment by María Luján — 29 October, 2008 @ 3:48 am
Well, Do´C Case controls demonstratred the link between tobacco and lung cancer. There are several case controls published in ASd related to CMPs .The table 1 lists other things besides the hypothesis for testing:
To describe a newly recognised adverse reaction or interaction
To provide evidence of an association [30]
To generate hypotheses
To test hypotheses
To demonstrate diagnostic techniques
To elucidate mechanisms
To elucidate or suggest methods of management
To remind or educate
To enable systematic review
Of course there are improvements to made, especially in the analysis of the reports of case-controls and case reports-especially in terms of the amount of infomration needed-, but the epidemiology of large cohorts has its own problems to address.
Yes I read it. I complain about your
“you’re inclined to think that “specific anatomical location or pattern of injury” applies to autism”
Thanks , fortunately something I have - following my collaborators opinions- is an incredible ability of reading.
This is your generalization.I was thinking in the CMPs in some subgroups of ASD- especially the fingings of the activation of the innate immune system- such as VArgas et al or many others findings.Even more, here what is going on is the discussion of adverse reactions to vaccines and what importance the parental reports has in that context. Looking at vaccines as medications the polypharmacy problems and the adverse effects discussion apply.
For example, I guess you didn´t hear or read about the alum and the inflammasome or the macrophagic myofasciitis.
Comment by Do'C — 29 October, 2008 @ 7:49 am
María, your complaint is misplaced. I wrote, “If you’re inclined to think…”. This is not a generalization.
Incorrect María, what is going on is the discussion of alleged adverse reaction to vaccines.
Comment by María Luján — 29 October, 2008 @ 9:05 am
You send me to read more IF…well my thinking is much complicated than you presented and takes into account many aspects.
I wonder why the answer is related to “If you think this do that” in advance instead of asking….but I disgress.
About alleged adverse reactions to vaccines there is a lot for comment. In my personal experience, all is alleged and nothing deserves attention from doctors related to vaccines if your child is not with a seizure or in front of a death- threatening condition. The problem of the detection of correlation vs coincidence vs true causation is complex but at least it seems that some are hearing to address what is happening instead of what is alleged to happen ( for yes or not)
The “Environment” for Autism Research:
Signs of Improvement?
Comment by Calli Arcale — 29 October, 2008 @ 10:43 am
Maria:
In theory, yes, but the thing is, it’s often hard to catch the criminal in the act. One doesn’t generally witness chemicals moving through the blood, reacting with other chemicals, being metabolized, producing unexpected metabolites, damaging certain cells, etc. What one witnesses in an adverse event is not analogous to seeing a guy in a mask robbing a bank and shooting the teller in the head. It’s more analogous to seeing someone unfamiliar in your neighborhood and later discovering that your house has been burgled. The two events may be related, or they may not. More investigation is required to determine whether the unfamiliar person actually broke into your house and took your stuff.
Some adverse events are obvious, like anaphylactic shock, though even then it can be unclear what exactly the person is reacting to. You can tell they’re reacting to *something*, but what? There may be half a dozen chemicals in the pill they took; which is to blame? Or maybe the local burger shop uses the same oil for fish and french fries and the person happened to be taking the pill along with a packet of fries from the drive-through and is violently allergic to fish. It happens.
With the alleged vaccine-autism link, the connection is even more tenuous. In nearly all cases, all that is known for certain is that the child started to display overt autism symptoms around age 3, and around 3 they got their regular vaccines. Confounding the issue, some common side effects of vaccines (such as fever) can fool a person into thinking that a seriously bad event has occurred, and then assume that anything else bad is part of that bad event. To go back to the house burglary analogy, it would be as if you saw a strange man, your house was burgled, and a neighbor’s house burned down. The burglary and the fire may be unrelated. It’s suspicious enough to warrant investigation, but one cannot assume they are related.
Adverse events should never be taken lightly. But at the same time, the medical profession has a duty to the public to make decisions based on what is *known* rather than merely what is suspected. In my burglary analogy, if the assumption is made that the strange man burgled your house and burned down your neighbor’s house, he might go to jail, and next month the *real* burglar will strike, and the month after that, another house will burn down because nobody’s realized that all the houses on your block have a common wiring defect — nobody looked into it, because they just assumed the seemingly obvious conclusion was correct.
Doctors need to be respectful of parents’ observations and opinions. That doesn’t mean they should treat them as always completely accurate.
Comment by passionlessDrone — 30 October, 2008 @ 5:46 am
Hi Callie Arcade -
With the alleged vaccine-autism link, the connection is even more tenuous. In nearly all cases, all that is known for certain is that the child started to display overt autism symptoms around age 3, and around 3 they got their regular vaccines. Confounding the issue, some common side effects of vaccines (such as fever) can fool a person into thinking that a seriously bad event has occurred, and then assume that anything else bad is part of that bad event.
I am not sure this is necessarily all the we know.
It turns out, we have evidence that children with autism are more likely to have their toll like receptors overexpressed when compared to normal children. It is these components of the immune system that are critical towards the generation of an immune response; the presence of aluminum based adjuvants in a vaccine are there precisely because they trigger these toll like receptors.
Take a look at this study:
Macrophage Migration Inhibitory Factor and Autism Spectrum Disorders
I’m not linking, as it seems to get caught up in the spam filter. That’s OK, you can find it.
Anyways, what we have here is evidence that some children with autism are genetically predisposed to have more of a substance known to overexpress key components of the immune system. A correlation exists between the level of this chemical and autism severity across several measures.
This doesn’t prove vaccines ’cause’ autism, but does give us a biochemical mechanism of action for what some people have been claiming they have observed; children with autism who experience extreme reactions to vaccinations.
There also seems to be some applied evidence of differential cytokine production when toll like receptors are triggered via agonist when comparing autism and non diagnosed children.
See:
Evaluation of atopy and immune functions in children with autism
Again, not linking for filtering purposes.
- pD
Comment by María Luján — 30 October, 2008 @ 7:23 am
Well, calli, following with the idea that pD presented, there are several other pathways of research that have not been explored, related to a dysfunctional immune system and altered answers to immune stresssors… and many findings in ASD of a dysfunctional immune system
Neuropsychobiology. 2002;45
Activation of the inflammatory response system in autism.
Croonenberghs J, et al.
Brain Behav Immun. 2008 Aug 14.
Altered gene expression and function of peripheral blood natural killer cells in children with autism.
Ashwood P et al.
Alum mechanism of immune activation has been recently finally dilucidated, at least partially.
Nature. 2008 Jun 19;453(7198):1122-6.
Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants.Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA.
and the inflammasome is being activately studied in inflammatory and autoinflammatory medical conditions, such as the innate immune answer arm, from the molecular biology -genetics and mechanistic point of view.
Comment by sigma — 31 October, 2008 @ 7:25 am
Offit said there were 16 studies that compared “hundreds of thousands” of vaccinated children with “hundreds of thousands” unvaccinated. I have never seen one or even heard of a study like this. It seems to me that the medical community has avoided this type of study.
What we apparently do know is that autism does not have 1 or 2 or 3 genetic causes. It appears to be 100+. It seems unrealistic to assume that in these 100+ genes that nothing in the environment comes into play. No facts. Just good old common sense.
While the anti-vax crowd will never believe any study showing no connection, it is time for the medical professsion to do a real study like the one Offit says has been done 16 times. The truth is that there is no sound study comparing apples-to-apples, except for vax schedule. The one study that purports to do this was clearly manipulated to get the desired results.
If the lawyer is right about his son, there will be a correlation. If he is wrong, the link will be weak or worse.
Comment by Do'C — 31 October, 2008 @ 10:38 am
That’s not what he said - it’s an extremist interpretation. He described the process of epidemiology with an example of one vaccine conflated with the overall process. A little sloppy, I’d agree. While his explanation was not clear that the comparison of vaccinated to unvaccinated for any vaccine (or preservative) is often within differing vaccination rates within a study population, you don’t have to be rocket scientist to understand the faulty ethics and lack of feasibility of what you suggest.
If you’d like to comment on the actual topic (which is special pleading by anecdote in a scientific context), feel free. Otherwise, please go be a troll somewhere else.
Comment by sigma — 31 October, 2008 @ 7:53 pm
[Continuation of off-topic drivel removed]
Comment by María Luján — 1 November, 2008 @ 2:53 pm
“The plural of anecdote is not data” (better “the plural of anecdote is probably not data”) BUT
“The singular of data is anecdote”
From The Social Science Statistics Blog
Now, how much has the so called “scientific approach” in autism-that it seems correlated to recommend phsycological advice- for the family-, OT and ST (EEG and MRI)- helped individual autistic children- who demonstrated later to have specific CMPs?For my son, almost nothing.. FWIW, my personal anecdote. Therefore, what it matters, what is told as theory based on partially accepted EBM related to the paradigm adopted in general or what finally helps-found going against the theoretical and EBM recommendations because of the criteria of the doctor in front of the individual patient- hearing his/her parents concerns?Of course the outcome depends of many aspects-risks/benefits proper analysis, safety considerations, familiar positions on many issues.but there are as many families of autistic people as autistics and every doctor is different also.Of course there is a lot of responsibility of parents going on in the difficult waters that this situation presents; of course nothing is simple or fast or confortable- at least in my experience. Of course you have to analyze in pieces what is said to you, how , with what detail or atttitude, to trust nothing and to challenge (almost) everything.But one thing is the medical researcher doing things in a lab and the other the doctor in practice.
It is diagnosed only what is known/ searched and tested. Because the anecdotes have not been properly systematized and analyzed, a protocol of CMPs-enough complete- in ASD is not even in the beginning of being discussed in traditional mainstreamed ambits-except in very obvious cases and not adopted as protocol. Forget the cause/cures discussions, the real medical problems that today many autistic people like my son has remain unattended by the “classical” approach and its dispise of anecdotes as unuseful- in the paradigmatic view of autism as mainly genetics and vaccines/antibioticas as safe for all. Only when the doctor forget the controversy and the paradigm and the opinion´s book and the epi-although not the research peer reviewed journal-, and look to his /her patient with respect but also with interest to know what is happening-clinically, metabolically, biochemically, systemically but also emotionally- beyond the dogma, therefore a possibility of real help is present. And in the case of children it is very important is to hear the parents .
I read some time ago something that applies for me about how I have found the best doctors for my son. Considering doctors-peditricians or others- they should hear my autistic son with their eyes and they should see him and pay attention to what they hear. .now where is THAT written in the EBM book?
And a reflexion I found on topic, thinking in those (doctors) who heard/hear us (parents of autistic children telling anecdotes)although not necessarily they agree with us:
Link
Comment by María Luján — 2 November, 2008 @ 8:53 am
As you know, case reports are just over anecdotes in the general picture of EBM, however, there are recent presentations of a new vision of the case report
Otolaryngology - Head and Neck Surgery
Volume 138, Issue 3, March 2008, Pages 261-264
Practical guide to understanding the value of case reports G. Neely et al
“This article describes the value of case reports to medicine, citing 3 examples that have significantly improved the practice of medicine. We also provide criteria for effective reporting, which include the elements of both surprise and closure.
In summary, we offer support for the contention that case reports are fundamental to the scholarly practice of medicine and enhance the intent of a quality medical journal.”
AND
Case reports
“Case reports and case series may be the ‘lowest’ or the ‘weakest’ level of evidence ‘of a cause’, but they often remain ‘the first line of evidence of what happened’. This is where everything begins.
Citations from the Editorial
Editorial Why do we need Cases Journal? Richard Smith from here thereafter
” As Sir Michael Rawlins, chair of the National Institute of Health and Clinical Excellence, showed at a workshop two years ago, follow the NICE guidelines for each condition and the patient will end up in a mess - because NICE guidelines don’t deal with comorbidities. More profoundly, they probably never can: the guidelines are based on trials that deliberately excluded patients with comorbidites. You can never do randomised trials on every kind of patient - the patients that GPs meet every day of the week”
“Ben Shneiderman has written recently in Science magazine about the need for what he calls Science 2.0 [17]. Science 1.0 of hypothesis generation and testing remains important, but Science 2.0 will help us understand “challenges [that] cannot be studied adequately in laboratory conditions because controlled experiments do not capture the rich context of Web 2.0 collaboration, where the interaction among variables undermines the validity of reductionist methods”. Shneiderman B: Science 2.0.
Science 2008, 319:1349-50
Reductionist methods struggle with the problem of comorbidities and fail to recognise that patients are much more than specimens with a collection of disease but rather complex individuals with their own values. ”
“Alejandro R Jadad and Murray W Enkin, two of the great advocates of randomised trials, have written: “Our main wish, from which all others stem, is that RCTs be taken off their pedestal, their exalted position at the top of an artificial evidence hierarchy, that all forms of evidence be appreciated for what they can offer” “Jadad AR, Enkin MW: Randomized controlled trials: questions, answers and musings. Oxford: Blackwell Publishing; 2007.
Comment by uncwizard — 26 April, 2009 @ 8:22 am
Just happened to be checking on signs and symptoms of swine flu.
Came across ” Cytokine Storm-fatal immune reaction-when immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of the infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally, this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader.”
Is not injecting a small child with multiple vaccines of live and killed viruses an invasion of the child’s immune system? Not of just one to fight off, but of many? Do the pediatricians not tell us to keep the sick away when we bring our newborns home with us because they have weak immune systems, but yet they give the newborn a vaccination of Hep B in their heel, the second day in the hospital? Does not a family history of autoimmune disorders mean anything when vaccinating these children? Have these pharmaceutical companies even bothered to research their own drugs to see what might be triggering these reactions, what additive or biological reason these kids are considered fine, then the shot, the reaction, then the regression? No! They are PROTECTED! Not the kids.
None of this seems to matter I guess in the pharmacuetical world, as long as they pass out their kick-backs along to the doctors everytime a child is vaccinated. Has anyone come across the treatment or prevention of a cytokine storm–OX40-IG.
Needless to say, these pediatricians give you a SLIP of paper with a short symptoms list of possible high fever, persistent crying and a few more and if you call, “Oh just keep an eye out, if things aren’t better tomorrow……”
My nephew had a severe reaction to his 18 month shots…..the reaction started within an hour or two after receiving his multiple shots….high pitch screaming, banging his head…..he WAS a normal developing baby…..walking, talking, even above normal developement in some areas….So, yes, parents should be allowed to tell their story because it is evidence to what led up to their child’s autism. Anyone who says differently is trying to hide something.
The general public is not as niave as we are being depicted….but it is sad that we have to go through personal experiences before we think to educate ourselves. And that is, because we are led to believe that the medical community is suppose to protect us…”First, do no harm….” I guess ethics is swept under the rug and so is all the dirt when it comes to the pharmacuetical companies and all those who profit from it. Has any parent ever been given the inserts of the vaccinations their child was about to receive? I had to ask for it and the PA acted like she didn’t have a clue what I was asking for after persisting I finally got it, refused my childs shots, because that wasn’t even the reason we had gone in that day.
It makes for a very interesting read, don’t forget your magnifying glass!!!!!!! If your child falls into the small percentile category that it goes over, I guess your child is just in the SOL category and your child gets the shot anyway. If these inserts were posted on the news and in big print in the doctor’s offices, I KNOW, parents would be rejecting these vaccinations. I could go on and on, because everytime I get on this subject I just get SUPER angry all over. To know, my nephew, now about to turn 10, was a happy, healthy developing boy, is severly autistic because some people decided that, overall it’s okay to subject a child’s immune system to such havoc, over such a short period of time no matter what the circumstances might be!!!!!!! Money!Money!Money!