Where are the monkeys?
February 12th, 2010
[Kudos to KWombles who alerted me to this story]
This morning, when I went to find the Hewitson et al (2009) article in the journal Neurotoxicology - the article that had been the inspiration for my post “A ‘Made for Court’ Study?” - I found that it had been withdrawn (see here).
Given that there has been a recent cry of “Show me the monkeys!” from “the usual suspects” in anticipation of the next episode of Hewitson et al, I find the withdrawal of their first paper intriguing. I can’t help but wonder if this is somehow related to the results they intended to publish in their second paper - the one that “the usual suspects” have been crowing about.
The Pollyanna part of me (a very small part, I assure you) wants to believe that the authors have withdrawn the paper in order to correct its many serious flaws. Of course, this would require not just a simple re-write but a complete redesign of the study and starting again from scratch - rather like “remodeling” a house by tearing it out, foundation and all, filling in the hole and starting over. This may be the case.
Another possibility is that they want to re-do their statistical analyses and conclusion, since their data show not only that they cannot distinguish between thimerosal and the hepatitis B vaccine as a cause of the “neurodevelopmental abnormalities” but also that they can’t actually say that there was any significant difference between the treated and control groups. After all, negative results are results, too.
However, I suspect that the real reason may be that the editors of Neurotoxicology took a long, hard look at the paper and decided that it wasn’t worth publishing, after all. Some small (or large) part of the impetus behind that decision - if that is, indeed, what happened - might be the recent conclusions of the GMC regarding the “anchor” author, Andrew J. Wakefield. That’s not the best reason to withdraw the paper, but it’s better to do the right thing for the wrong reasons than not at all.
Whichever way it turns out, the “Show me the monkeys!” cry is going to sound a little more hollow now that the first article of the series has been withdrawn.
Doubtless, the first act of “the usual suspects” will be to paint this as part of the “massive conspiracy to supress the Truth about autism”. However, Neurotoxicology has been very sympathetic to the “something-in-vaccines-causes-autism” movement, publishing several low-quality studies by people (not necessarily even researchers - see this one) who feel that vaccines somehow cause autism, so it’s a bit of a stretch to start screaming that they are “censoring” autism research now.
We (or, at least, I) don’t know why the article was withdrawn, and it may be for reasons that I’ve not contemplated. But having an article withdrawn after being accepted is never a good thing. Again, I hope that it was withdrawn by the authors because they have read the criticisms about their study and want to re-write it to correct their mistakes. Of course, even though I hope that is the reason, I realise that isn’t the most likely reason. Only time will tell.
Meanwhile, where are the monkeys?!?
Prometheus
Filed under: Autism Science | 8 Comments »
Stem Cell Therapy for Autism
January 26th, 2010
Sorry to have been gone for so long, but I wanted to take extra time on this topic because….well, because it needs extra time and attention to detail.
In growing numbers, people are taking their autistic children to “clinics” - in Costa Rica, in Germany, in Russia - to get “stem cell” injections. I put “stem cell” inside inverted commas because it is not entirely clear that what these children are receiving are actual stem cells.
And that might be the “good news” in this post - more about that later.
Stem cells have been in the news a lot, especially the past year, since President Obama cleared the way for embryonic stem cell research. So, today, almost everybody above the age of three has heard of them - but how many people really know what they are and what they can (and can’t) do? Not so many, I think (based on what I’ve heard people say about stem cells).
What are stem cells?
Judging by the many and varied things that the lay press have said about stem cells, you might be forgiven for thinking that they are magical little beings that swim to the site of whatever medical problem exists and fix it - sort of like the “nano-machines” that periodically crop up in science fiction stories. However, sad to say, that isn’t the case.
Stem cells are nothing more than a type of cell that can differentiate (develop into) a different type of cell - sometimes many different types of cells (and can proliferate - divide - indefinitely). Far from being magical semi-sentient beings, they are quite prosaic and exist in your bone marrow, under your skin, in your brain - pretty much everywhere in your body. They range from the humble karatinocyte stem cell of your skin - which can only produce karatinocytes (the outer layer of your skin) - to the omnipotent stem cells present in the first few cell divisions after fertilization, which can each develop into a complete organism (see: “identical twins”).
What has some scientists excited about stem cells is the potential to use certain types of them to treat illnesses and injuries that are currently beyond our abilities. In a few cases, we have already seen these therapies work - in most cases, they remain tanalizingly out of reach.
There are a number of different types and degrees of stem cells, which complicates the discussion considerably. The cells of a zygote (fertilized egg) that is still in its first few cell divisions can each become a complete organism (as mentioned above), but before long (a few hours, in most cases), those cells have differentiated to the point where they can’t make an entire organism, but they can still produce cells of any tissue or organ of the body. Once they have “committed” to going down a particular developmental path, they cannot (usually) go back (without our “help”). Eventually, the differentiation process progresses to the point where the cell is terminally differentiated - it has become a liver cell or a neuron and it will not (again, usually) become anything else.
There are two general features of a terminally differentiated cell: it can only divide a few times - at most - and it cannot generate or develop into a different type of cell (again, in biology, there are always the rare exceptions to this and every other rule).
Unipotent and multipotent stem cells:
In order to deal with cell death due to injury or senescence (”wearing out”), most tissues and organs have a pool of unipotent and multipotent stem cells. Unipotent stem cells - as the name implies - can generate one type of cell (e.g. the keratinocyte stem cell can only make keratinocytes); multipotent stem cells can generate a range of related cell types. A good example of multipotent stem cells are the marrow stem cells, which can generate any of the blood cells - red cells, white cells (all types) and platelets - but cannot make, for instance, neurons or skin cells.
Pluripotent stem cells:
This is the type of stem cell that most of the media “hype” is all about. These stem cells can develop into any cell type from any of the three germ cell layers. These are not found in significant numbers beyond infancy, although there have been a number of studies showing that they do persist (in small numbers) into adulthood.
One of the major breakthroughs in stem cell research - and one that might not have happened this soon without the politically-motivated ban on embryonic stem cell research - has been the ability to take adult cells [Note: in stem cell research, cells become "adults" shortly after birth of the organism.] and “reprogramme” them into pluripotent stem cells. This not only gets us around some rather sticky moral and political controversies, it also gets us around the problem of the immune system. More about that in the next section.
Embryonic vs Adult stem cells:
The next classification of stem cells refers to their origin. Thus we have embryonic stem cells (ESC) that come from the inner cell mass of an embryo, adult stem cells (generally multipotent stem cells) and induced stem cells (iPSC, iMSC) that are made from either adult stem cells or somatic (terminally differentiated) cells.
How do stem cell therapies work?
Adult stem cells - generally marrow stem cells, since they are easiest to “harvest” - have been used for some time in the treatment of leukemia and lymphoma. They have even been used - with significantly less success - in the treatment of breast cancer and brain cancer. The reason that bone marrow stem cells are so useful is not because they have some magical anti-cancer activity; they simply allow the oncologists to use much higher doses of chemotherapeutic drugs. One of the limiting factors in chemotherapy for cancer is the bone marrow - higher doses run the risk of killing off too much (or all) of the bone marrow stem cells, killing the patient (usually due to infection from low white blood cell count - red cells and platelets can be transfused).
By taking out some of the patient’s own bone marrow stem cells and saving them, they can be re-infused after the chemotherapy has been completed - in essence, they “re-seed” the marrow. This allows them to use much higher chemotherapy doses, which (in some situations) can make the difference between a relapse and a remission.
A similar process is used - experimentally, for now - in the treatment of multiple sclerosis [1]. Multiple sclerosis is an auto-immune disease, where a group of immune cells are reacting to the patient’s own tissues (the myelin covering of their nerves, in this case). Recent advances in cell identification and sorting have allowed researchers to isolate only stem cells from the marrow (and none of the terminally differentiated cells that are causing the problem). After the stem cells are removed, the patient receives a course of chemotherapy (and occasionally radiation) to kill off the immune system, after which the stem cells are re-infused to “re-seed” the marrow with (hopefully) healthy cells. This appears to be somewhat promising in limited trials to date, but it is far from established therapy.
A bit more experimental is the use of stem cells to repair damaged tissues, such as heart muscle, nerves (spinal cord) and brain. To do this you need pluripotent stem cells (or you need to extract the stem cells from the tissue/organ - a technique that hasn’t been developed yet). You can use either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC). So far, the few clinical trials using stem cells for cardiac disease are either in the early stages or not yet started.
Early on in stem cell research - before the discovery of techniques to induce terminally-differentiated adult cells to become pluripotent stem cells - it was thought that only embryonic stem cells were pluripotent. But studies (and a few clinical trials) using embryonic stem cells ran into problems with the immune system. Embryonic stem cells (unless they were harvested from the patient’s umbilical cord blood or a genetically identical donor) are foreign to the recipient, so there is the problem of rejection so familiar in organ transplants, where the recipient’s immune system attacks the stem cells. If the stem cells are (or differentiate into) immune cells, they can even turn about and attack the recipient’s cells, a phenomenon known as graft vs host disease. Either situation calls for immune suppression, which limits the usefullness of embryonic stem cells.
The advantage of using iPSC’s is that they are (usually) the patient’s own cells, so there is essentially zero chance of rejection or immune reaction. Of course, if the problem is a genetic one, there is probably little point in using the patient’s own cells, since they will carry the same mutation.
Unfortunately, iPSC’s carry some “baggage”, as well - literally. In order to “reprogramme” adult cells to become iPSC’s, certain genes - that have been permanently inactivated in terminally differentiated cells (and even in multipotent stem cells) - need to be “turned on”. Initially, this was done using lentiviral vectors - retroviruses that had been “engineered” to carry non-inactivated versions of the four critical genes (Oct3/4, Sox2, c-Myc and Klf4) into the cells and insert them into the DNA [2]. This worked very well, but the problem is that lentiviruses are rather….indiscriminate about where they insert themselves, so there is a chance that they will do so in a place that inactivates a critical gene. This is why so many of the lentiviruses are known as oncoviruses (cancer-causing viruses). As you might imagine, this limited the use of iPSC’s to experimental animals.
More recently (2008), a research team has managed to convert embryonic fibroblasts to iPSC’s without using a viral vector, using plasmids [3] and even more recently, another team managed to do it with proteins alone [4]. Both of these techniques are - needless to say - still being refined and are not ready for clinical trials.
So, if anybody is getting “stem cell therapy” today, it is either from their own bone marrow (and will produce only blood cells) or it is from embryonic stem cells (and carries the risk of rejection and/or graft vs host disease).
Risks of stem cell therapy:
The risks of stem cell therapy are hard to quantify because it is difficult to separate the risks of the other parts of the therapy from the risks of the stem cells. This is because most of the patients who have undergone stem cell therapy to date have received bone marrow stem cells (their own or someone else’s) and have also received large doses of chemotherapy and/or radiation, which muddies the water as far as following the risks of stem cell infusions goes. However, there are some “brave maverick doctors” in places like Russia who are injecting embryonic stem cells into the spinal fluid of children with ataxia-telangiectasia (and, apparently, other genetic neurological disorders). The outcome of one of these children was reported in PLoS Medicine:
“In May 2001 at the age of 9 y, in March 2002 at the age of 10y, and in July 2004 at the age of 12 y, he was taken by his parents to be treated in Moscow with repeated transplantation of fetal stem cells.”
Approximately one year after his last stem cell treatment, he was seen in hospital:
“…[he] presented to the Sheba Medical Center in February 2005 with recurrent headaches. On examination he had severe neurological deficits characteristic of AT, affecting mainly his motor functions and making him wheelchair bound.”
Although not explicitly stated in the case report, the stem cell treatments were apparently not working, based on their description of his condition. What they found, however, was worse than “not working”:
“MRI performed in February 2005 to investigate the headaches revealed a right infratentorial lesion slightly compressing the brain stem and another lesion at the cauda equina (Figure 1A and 1B). The lesions grew slowly as evidenced by repeat MRIs in June and July 2006. In September 2006 at the age of 14 y, surgery was performed and a tumor localized at L3–4 level attached to the cauda equina nerve roots was removed. Additional ’satellite’ lesions were identified attached to nerve roots rostral to the main lesions (Figure 2A and 2B).”
In short, this lad had two separate brain and spinal cord tumours. Under the microscope, these tumours were not cancerous, but looked like disorganized neural tissue. When they were tested genetically, the tumours did not match the patient’s genetic markers. They were, in fact, from two separate donors.
Although this child received embryonic stem cells from two different donors, there is no reason why the same problem couldn’t happen with either autologous embryonic stem cells (i.e. from stored cord blood) or iPSC’s. In fact, one of the defining characteristics of pluripotent stem cells (embryonic, adult or induced) is there ability to form teratomas - tumors containing tissues from all three embronic layers (ectoderm, endoderma and mesoderm).
What about using stem cells in autism?
Part of the problem with using stem cells to treat autism is that we don’t know what we are treating. Despite the enthusiastic promotion of various “theories” about what causes autism, there is no generally agreed upon pathology or “lesion” to treat. Even genetic studies fail to show one single genetic cause of autism, suggesting that what we call “autism” is a number of different disorders with a similar (or not so similar) appearance. Injecting stem cells in the vague hope that they will find the problem and fix it is foolish. Stem cells have no more idea of how to “fix” autism than we do - which is to say, “none”.
The “good news” I referred to above is that, based on the descriptions of what they are doing, the clinics where parents are taking their autistic children for “stem cell therapy” are using - at best - multipotent blood stem cells. The descriptions are more promotional than informational, so it is entirely possible that their “techniques” are yielding no stem cells whatsoever. This is “good” because infusing real pluripotent stem cells into the blood or (worse yet) into the spinal fluid carries the risk of creating tumors without any known (or even suspected) potential for benefit.
In the event that someone invokes the concept of “neuroinflammation” as a reason to try stem cell therapy, I’d like to point out that, to date, effective stem cell treatments for “neuroinflammation” and autoimmunity have involved also giving large doses of cytotoxic drugs to kill the errant immune system cells prior to re-infusing the patient’s stem cells. Explain how that would work without the cytotoxic drugs (or radiation) and you’ll get a Nobel Prize in Medicine.
I fervently hope that none of these clinics are using viral vectors to create or “activate” pluripotent stem cells, as this carries a known risk of carcinogenic transformation. I know that they aren’t using any of the non-viral techniques because they are too new and too complicated. I suspect that they are simply re-infusing the patient’s own blood. And I hope that they are using good sterile technique when they do so.
At best, “stem cell therapy” for autism is offering false hope; at worst….. who knows?
Prometheus
UPDATE: See this article in the Milwaukee Journal Sentinal about the sales techniques used by a stem cell therapy center.
References:
[1] Capello E, Vuolo L, et al. Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks. Neurol Sci. (2009); 30(Suppl 2):S175-S177
[2] Takahashi K,Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. (2006);126:663–676
[3] Okita K, Nakagawa M, et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science. (2008); 322:949-953
[4] Zhou H, Wu S, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. (2009); 4(5):381-384
Filed under: Autism Science, Autism Treatments | 17 Comments »
Is DMSA safe and effective?
November 26th, 2009
Yes!
For lead poisoning.
And probably as a treatment for mercury and cadmium poisoning (but not for assessing the body burden of mercury).
And possibly as a treatment for arsenic and antimony poisoning.
But as a treatment for autism, it hasn’t been shown to be either effective or safe, despite the titles of two articles (or one two-part article) in BMC Clinical Pharmacology.
These two articles, published by a diverse group of authors - including Professor of Materials Science and Engineering James B. Adams, PhD (lead author), DAN! practitioner Jeff Bradstreet, MD and Professor of Pediatrics and Section Chief of Pediatric Allergy, Immunology and Rheumatology, Jane El-Dahr, MD - are titled:
Strangely enough, given that the lead author is on the faculty of Arizona State University and the “anchor” author is on the faculty of Tulane University, the study was done under the auspices (and approved by the IRB of) Southwest College of Naturopathic Medicine - which Dr. Adams lists as his academic affiliation in these articles.
Curious.
It’s almost as though they couldn’t get a real university IRB to approve their study. After all, Tulane University has an IRB, and so does Arizona State University, but they decided to go with the IRB at a naturopathic college, instead.
Again, that’s curious.
But that’s not the last curious thing about these studies. In fact, the next curiousity about these studies is the very…..eccentric nature of the study design.
Let me start by outlining the odd and circuitous path of their enquiry into the safety and efficacy of DMSA as a treatment for autism.
Perhaps it is the writing style or maybe it is the chaotic nature of their research showing through in the articles, but it is very hard to track exactly how many subjects were in each of the several “phases” and sub-phases of this study. Here is what I could extract from their writing:
The study began with 82 autistic children, ages 3 - 8 years, who underwent a physical examination, blood tests for kidney and liver function, blood counts, and red blood cell (RBC) glutathione. If the examination and blood tests (with the exception of RBC glutathione) were within normal range (the article uses the phrase “not below the normal range” - curious), they were “eleigible to participate in Phase 1″.
Each parent filled out an initial Autism Treatment Evaluation Checklist (ATEC - a test devised by Drs. Rimland and Edelson and never properly validated) and a “Heavy Metal Exposure Questionnaire”. The parents also collected a “baseline first-morning urine sample” - for “heavy metal testing”. (three guesses which lab did the testing)
Here’s where it gets weird: the next step was to randomly divide the subjects into two groups. One group got a glutathione-containing skin lotion (to be applied once a day for a week) and the other group got a placebo lotion. At this point, I found myself asking, “What’s up with the lotion? Who’s selling the glutathione lotion?“, because this meant that - at best - their results would be much harder to interpret.
Further complicating the study, they had every subject receive a single “round” of oral DMSA (10 mg/kg/dose, three doses a day for three days - nine doses in total) to test their “heavy metal excretion” (and here I thought that autistic children were “poor excretors”). Only those subjects who had post-chelation urine “toxic metals” (as defined by “Doctor’s Data Laboratories” - aluminium, antimony, arsenic, beryllium, bismuth, cadmium, lead, mercury, nickel, platinum, thallium, thorium, tin and tungsten) greater than the 95th percentile (for people who had not received a chelating agent) continued on to “Phase 2″. (see: Mercurial Laboratories for a more in-depth discussion)
Amazingly, eight (8) children had all of their “toxic metals” below the 95th percentile even after chelation. This deserves to be a published result on its own! In all, 17 subjects failed to complete “Phase 1″ (testing, glutathione lotion and one “round” of DMSA), leaving only 65 (79%) to move on to “Phase 2″.
In “Phase 2″, the subjects who had recieved the glutathione lotion were scheduled to receive oral DMSA and those who had received the “placebo” lotion received a placebo capsule. This was to go on for an additional 6 “rounds”, each “round” consisting of three days of 30 mg/kg DMSA (divided into three doses) followed by eleven days of no treatment. The article is a bit confusing about this, saying that the subjects took the DMSA or placebo for “…up to 3 rounds” in one place and a few paragraphs later saying that “When the participants finished Phase 2 (after either 3 or 6 rounds)…” The reason for this is that urine testing was done after the second “round” of DMSA in Phase 2 (third “round” total) and those who were not continuing to excrete elevated levels of “toxic metals” after three “rounds” of DMSA were considered to have completed Phase 2. Why some had an additional “round” after this testing is unclear.
Before entering Phase 2, the 65 remaining subjects underwent further blood tests and also had the ADOS administered. The ADOS testing found that 7% of those who completed Phase 2 did not meet the criteria for Autistic Spectrum Disorder - we are not told how many of those entering Phase 2 failed to meet criteria. The authors did not seem particularly bothered by the fact that 7% of their subjects were apparently not autistic or on the “autistic spectrum” - they explained this away by stating that “All children continued on in the study, since they all had a previous clinical diagnosis of ASD.” [emphasis added]
In addition to the ADOS, the parents filled out the Pervasive Developmental Disorders - Behavior Inventory (PDD-BI - a screening test evaluated only by its originators) and the Severity of Autism Scale (SAS - a test developed by the authors and not validated).
Following completion of Phase 2, the 41 remaining subjects (50% of starting subjects) underwent repeat blood testing and an ADOS evaluation. The parents filled out the ATEC, PDD-BI and SAS questionnaires again, as well as a Parental Global Impression (PGI - a new test not yet validated) questionnaire.
Let’s recap the study so far:
The study consisted of three arms:
[1] Subjects who received placebo lotion and one “round” of DMSA - 15 subjects.
[2] Subjects who received glutathione lotion and three or four “rounds” of DMSA. It appears that five subjects were in this group - it remains unclear why some had three and some had four.
[3] Subjects who recieved glutathione lotion and seven “rounds” of DMSA - 21 subjects.
The testing consisted of RBC glutathione, complete blood counts, liver function tests, renal function tests, and urinary “toxic” and “essential” metal excretion as well as the ATEC (an un-validated test), PDD-BI (a screening test), the SAS (an unvalidated test), the PGI (new and unvalidated) and the ADOS (validated for autism diagnosis, but not severity rating).
The problems with this study are legion, but their results were the most damning part of the whole mess, because the results don’t say what the authors think they do.
Behavioral Testing:
In the behavioral testing, only the ADOS (which - as I mentioned before - is not valid for comparing autism severity) showed any diffrerence between the “got one round of DMSA and placebo lotion” and “got three to seven rounds of DMSA and glutathione lotion” groups. The other tests showed no statistically significant difference. Of course, the authors try to spin that as best they can, but the results speak for themselves.
Safety Testing:
DMSA’s safety was studied long before than this study, and its side effects are well known: reduction of white cell count (generally reversible), reduction in platelet count (generally reversible), liver injury (generally reversible) and some subtle decrease in intellectual function when given to children (and rats) with low (or zero) lead levels (not reversible).
The “safety testing” in these articles, strangely enough, did not include measures of the most significant (and the only irreversible) side effect that has been noted with DMSA, namely cognitive/intellectual functions (see: Dietrich et al and Stangle et al). Thus, in a supreme moment of irony, the authors have done exactly what some of them have long claimed that “the government” has done - failed to research the correct mode of toxicity.
The authors (and many, many other practitioners) are giving DMSA to children with low levels of heavy metals - exactly the group found to be at risk for permanent intellectual impairment. Yet they do no intellectual testing. They could have gone to Dietrich et al and read it right out of their paper, yet they didn’t.
Curious.
Biochemical Effects:
This area, which the authors call “Medical Effects” has the most bizarre results ever. Rather than spend the next year discussing them all, I’ll give my “highlights”:
[1] “Toxic metal” excretion.
Not surprisingly, lead excretion was up significantly - this is what DMSA does. However, in a major upset for the autism-is-mercury-poisoning hard-core, mercury excretion was fifth, after tin (?), bismuth (??) and uranium (????). Who knew that autistic children were so heavily contaminated with uranium? There was even more thallium excreted than mercury, over the inital “round” of DMSA administration.
While lead is still ubiquitous in urban areas - a legacy of decades of tetraethyl lead in gasoline, where are these children getting their exposure to tin, bismuth and uranium? Or is this yet another problem with the laboratory? The authors make a brave stab at explaining how their results differ from an earlier Bradstreet “study”, but it doesn’t really work too well.
[2] “Essential metal” excretion:
Several studies have looked at “essential mineral” excretion with DMSA administration - most have found that DMSA increases the excretion of zinc and copper to a minor degree. However, Adams et al found that potassium and chromium were the most significant losses during DMSA treatment.
Part of this comes from their…..eccentric way of looking at “essential mineral” losses as a percent of the RDA. This artificially elevates the “significance” of micronutrients like chromium (children in this age range should have about 15 micrograms a day).
The major problem with their analysis of this section is that they appear to have no idea how these elements get into the urine. Potassium, for example, is found in almost all foods and the urinary levels will fluctuate depending on how much there is in the diet and how much the body needs. DMSA has no effect on an alkali metal ion like potassium and the authors’ discussion makes it appear that their knowledge of basic physiology and biochemistry is inadequate.
[3] RBC glutathione:
This is a bit harder to interpret for a number of reasons. First off, the mean RBC glutathione doesn’t change significantly (it goes down in those treated with DMSA, but apparently not significantly). The baseline of all 72 subjects who had RBC glutathione done was a mean of 501 (+/- 246) - those 38 (this is confusing - which 38 are they referring to? Why not 41?) who went on to receive a second measurement in “Phase 2″ had a baseline mean of 523 (+/- 280). Two months after one “round” of DMSA, the ”38″ remaining had a mean of 478 (+/- 83). Another graph shows that those with higher RBC glutathione ended up with lower RBC glutathione after treatment and vice versa.
Secondly, their laboratory (Immunosciences) uses an odd “reference range for adults” - 427 - 714 micromolar (I assume it is micromolar - the article never gives the units - curious). There are a number of references (e.g. Richie et al 1996) that looked at large numbers of “normal” adults and found the range to be higher (670 - 1600 micromolar in whole blood; 1600 - 2800 micromolar in RBC’s).
There was also the problem of determining how the glutathione was measured. The authors state that Immunosciences Lab used an Oxis Research kit in which “…the absorbance measured at 405nm is directly proportional to the GSH concentration.” It may be nit-picking, but currently available Oxis Research glutathione measurement kits use absorbance at 400 nm, 420 nm and 412 nm - none use absorbance at 405 nm. Maybe it was an old kit.
Still, the change in the standard deviation of the RBC glutathione is curious (there’s that word again), but not terribly significant unless they can explain how reducing half of the subjects’ RBC glutathione is a “good thing”. Their presentation of the data raises more questions than it answers, such as “Why don’t you have RBC gluathione for all 41 subjects who completed Phase 2?” and many, many others.
Another point that the authors didn’t address about the RBC glutathione tests is that they don’t seem to show any positive effect of the glutathione lotion. Of course, they don’t break it out for us to show differences (if any) between the glutathione lotion and placebo lotion, but I suspect they would have if there had been any indication that the glutathione lotion had an effect.
[4] Platelets:
According to my university’s hospital lab, the “normal range” for platelets in children 3 - 6 years old is 204,000 - 402,000 per microliter of blood. This study showed that the baseline platelet count of their subjects who completed the study (n=41; I wish they would explain why the numbers keep bouncing around - I suspect it is because they didn’t get a full set of data on all of their subjects) had a mean (a rather useless value - median would be so much better) of 388,000 per microliter (+/- 274,000). Rather than give us a before and after number, they only give the percent above an below the “reference range” after one “round” of DMSA treatment. It’s almost as though they’re trying to hide something.
Figure 5 gives away part of the secret: like the RBC glutathione levels, the platelet counts show a reduction in standard deviation without a significant change in mean (or median - from my reading of the chart). While this may be an “interesting” (or “curious”) finding, it will take a lot more work to show that it means anything.
Bottom line:
These studies show neither efficacy nor safety of DMSA in the treatment of autism. This is not surprising, given the poor design of the study.
In fact, if I were to try to design a study that couldn’t show any results, I would be hard-pressed to do better than this one. The fact that the authors are so convinced that the DMSA did work is a testament to their pre-conceived notions.
In the end, this study gathered a bunch of data and then threw it against the wall to see what stuck.
And not much - if any - did stick.
Considering how long we’ve been hearing that DMSA treatment is dramatically ”curing” or “recovering” autistic children, the results from this study are distinctly underwhelming. It shows that there is no clinically significant difference between a single “round” of DMSA and multiple “rounds”, which suggests that DMSA doesn’t work at all. The authors’ assessment that a single dose of DMSA “did the trick” is a pathetic post hoc attempt at spinning the results in favor of their preferred outcome.
About the only thing it shows for certain is that glutatione lotion doesn’t increase RBC glutathione. But they didn’t address the efficacy of the glutathione lotion at all.
Curious.
Prometheus
Filed under: Autism Practitioners, Autism Science, Autism Treatments | 22 Comments »
A “Made for Court” Study?
October 24th, 2009
This month, the journal Neurotoxicology published a study about vaccines, mercury and neurolgical delay:
Hewitson L, Houser LA, Stott C, Sackett G, Tomko JL, Atwood D, Blue L, Railey White E, Wakefield AJ. “Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing Hepatitis B vaccine: Influence of gestational age and birth weight.” Neurotoxicology. 2009 Oct 2. [Epub ahead of print]
The full text of this article has been thoughtfully provided by the folks at “Thoughtful House” in Austin, Texas.
Normally, when I read a scientific journal article, I like to first know a bit about the qualifications and previous work of the authors. It helps provide a context to evaluate their methods and conclusions.
The Players:
Laura Hewitson:
Adjunct Associate Professor of Obstetrics, Gynecology & Reproductive Sciences and Environmental and Occupational Health at the University of Pittsburgh School of Medicine Pittsburgh Development Center Magee-Womens Research Institute.
She is also on the staff of “Thoughtful House” in Austin, Texas.
She has a PhD in Biology and has done a fellowship in reproductive biology
She is also mother to Joshua Hollenbeck, who is a petitioner in a lawsuit filed with the National Vaccine Injury Compensation Program (NVICP) [petitioner #437 of 828 – her name is misspelled]. With the hypothesis of autism being caused by the MMR vaccine alone or in combination with thimerosal in shambles (from the petitioners’ point of view), she has motivation to search out another hypothesis of causation to bring before the National Vaccine Injury Compensation Program (NVICP).
Carol Stott, PhD:
A psychologist who worked with Dr. Wakefield in the UK and later followed him to “Thoughtful House” in Texas. Famous for her harassing and threatening e-mails to Brian Deer (see here, here and here).
David A. Atwood:
Associate Professor of Chemistry and the University of Kentucky. He holds a patent (US patent # 6,586,600) on benzenediethanethiol (BDT) environmental chelators, one of which [N,N’-bis (2-mercaptoethyl)isophthalamide] is being marketed by Boyd Haley (also from the University of Kentucky) as “Oxidative Stress Relief” (OSR) and is touted to be a “cure” for autism, specifically treating the putative mercury toxicity widely assumed (but never shown) to cause autism. Dr. Haley is marketing OSR as a “dietary supplement”, even though it is not a substance found in food (or nature) and has not been adequately tested for safety as a drug. The FDA has objected to this, but the DSHEA prevents them from being able to prevent Dr. Haley from marketing this compound as a “supplement”, so long as he calls it a “supplement”. Dr. Atwood’s role in the marketing of “OSR” is unclear.
Lisa Blue:
One of Dr. Atwood’s graduate students.
E. Railey White:
As of 2007, an undergraduate at the University of Kentucky who worked with Dr. Atwood on the benzenediethanethiol (BDT) environmental chelator project – the product which later generated “OSR”
Andrew Wakefield:
A British gastroenterologist who has published a famous (infamous?) article linking the measles vaccine strain (found in the MMR vaccine) to autism. Unfortunately, that hypothesis has not been supported by independent data, with his “landmark” paper being marred by the withdrawal of most (ten of thirteen) of the authors on that paper.
Facing a General Medical Council investigation in the UK, Dr. Wakefield moved to the US, eventually settling at “Thoughtful House” in Austin, Texas.
Given the many of the authors’ past history, it seems odd that this paper doesn’t mention the word “autism” even once. That’s right - the word appears for the first time in the acknowlegments (in “Autism Research Institute”, one of their funding sources). Even with that apparent oversight, it seems apparent that the focus of this research is probably on linking hepatitis B vaccine – with or without thimerosal – to autism. So, now that we have a picture of most of the authors, let’s move on to the introduction of the paper.
Introduction – setting the stage:
The first question the authors felt compelled to answer in their introduction was why they were studying thimerosal-containing hepatitis B vaccine, given that this formulation hasn’t been available in the US since 2001. Their explanation was that thimerosal-containing hepatitis B vaccines are still available in “developing countries”, where they are needed because refrigeration isn’t as widely available as in the US. This is an important question for the authors to answer, because their research is moot, otherwise.
Methods:
This is where the study starts to show some “quirks”.
Although the authors don’t mention it, this study appears to be an extension of a study that has been underway for some time. It is amazingly similar to a study mentioned in a 2008 abstract. This is not - by itself - an issue; what is an issue is that while the number of treated animals remained the same (13) the number of control (untreated) animals more than doubled (from 3 to 7) since that abstract and the number of reflexes tested went from 18 to 13 (see also here and here).
Perhaps this could explain why the “randomization” and the control treatment in this study was so….eccentric. The authors make an off-hand mention of the unusual way they randomized their subjects, calling it “semi-random”. The rhesus macaque infants were grouped into “peer groups” that were less than four weeks apart in age – apparently sequentially. The infants were given either a thimerosal-containing hepatitis B vaccine (they had to add the thimerosal themselves) or – and here’s one of the ”quirky” parts – either no injection or an injection of saline (control). In this paper, three of the control animals received no injection at all and four received a saline injection - further evidence that the additional control animals were added only after the 2008 abstract.
Another ”quirky” part of the methods is their mention of each newborn being assessed by a “Simian APGAR” [sic] (NOTE: the “Apgar” score was developed by Virginia Apgar, MD in 1952 – the term is a proper name, not an acronym). This is odd because they never mention these Apgar scores again. Although they mention that the birth weights and gestational ages were similar between the treatment and control groups, they never, ever, mention the Apgar scores.
Curious.
The infant macaques were evaluated for the time it took them to develop ceretain reflexes: root, snout, suck, auditory startle, grasp (hands and feet, since macaques can grasp with their feet), clasp (hands and feet), auditory orienting, visual orienting (near and far) and visual following (near and far) – a total of thirteen reflexes.
The final ”quirky” thing about the methods is their choice of Laura Hewitson (”LH”) to perform the neonatal assessments [NOTE: as a reader pointed out, the neonatal assessments were done by "L.A.H." rather than "L.H." - my bad for not noticing that "Lisa A. Houser" was the "L.A.H." in question]. By their own admission, “L.A.H.” has no prior training or education that would make her a good choice for this job. In fact, she required training to be able to carry out the assessments. Perhaps it would have been better to hire one of her trainers to carry out the evaluations – this would have made the comparisons made at the beginning of the study comparable to those made later. As it was, we have no way of knowing where “L.A.H.” was on her “learning curve” when each group was assessed. This is critically important because it is pretty clear that a second control group was added much later.
The fact that the authors devoted almost a full paragraph to describing “L.A.H.’s” training is indicative of how vulnerable they felt on this issue.
Two important points to note before we leave the methods section - one is that the assessments were performed “..always daily…” (an odd choice of words). Remember that – “…always daily…”. The second is that there were 13 reflexes studied in this study, where there were 18 reflexes studied in the 2008 abstract. These points will be important later.
Results – the meat of the paper:
Again, the authors emphasize that the birth weights and gestational ages of the treatment and control groups were similar. Once again, they fail to mention anything about the Simian Apgar scores.
They found a statistically significant difference between the treatment and control groups on only three (3) reflexes (root, p=0.004; suck, p=0.002 and snout, p=0.03) and claim that startle (p=0.11) and grasp hand (p=0.07) “approached significance”.
Unfortunately, neither the methods nor the results mention any correction for multiple comparisons. After all, with a cutoff of p<=0.05 and 13 comparisons, there is a 48% probability that at least one of them will be “positive” (have a p-value less than 0.05) just by chance. If, in fact, they had originally looked at 18 reflexes, that probability rises to 60%.
The authors then did Cox proportional hazards regression analysis of the results (see here for a brief explanation) . This technique makes the assumptions that there is a proportionality between the “hazard function” (the mathematical function that describes the “hazard rate”) and the log-linear function of the independent variables (covariates). It also assumes that the relationship between the covariates and the hazard function does not depend on time.
The Cox analysis showed a relationship between exposure (to both hepatitis B vaccine and thimerosal, since they were administered together) and delayed root and suck reflexes, but not for snout. When they added gestational age as a covariate, they found a significant main effect of gestational age on visual follow far, which did not have a statistically significant independent difference between the two groups.
In the end, they found contributions of gestational age and “exposure” to the differences they saw in the time to acquire the reflexes.
This might be a good time to discuss the reflexes themselves. Human infants generally have the same reflexes (although they aren’t as dexterous with their feet), most of them (esp root, snout, suck, startle and grasp) present at birth. In humans, they are collectively referred to as “primitive reflexes”. It seems odd that human infants, who are generally “behind” the newborns of other animal species in their acquisition of motor skills, should have these reflexes at birth when the macques do not. I would appreciate any input from people who have experience working with primates on what this might imply.
Table 2 gives the mean time-to-criterion (the time it took the infant macaques to meet the “criterion” level of skill in that reflex) for all thirteen reflexes. One nit-picking detail I must point out is that even though the evaluations were done once a day, they show the results as means, using fractional days. This is deceptive (and very commonly done, yes I know) because it gives the impression of much higher precision than was attained.
For example, if one of the little macaques attained “criterion” in their suck reflex an hour (or even a minute) after the evaluation, they would have been “scored” as having taken a full day longer to reach “criterion”. This gives a particular “graularity” to the data and adds to the potential error. In the example given above, the difference between the actual time to reach “criterion” and the measured time would be almost 24 hours - more if the interval between evaluations was longer.
Another odd bit in this study is their graph of the results (figure 1), which shows that the evaluations were done at irregular intervals and not as described in the “methods” section (”…always daily…”). There were, in fact, several intervals that exceeded 24 hours and also many that were less than 24 hours. It may just be that their description in the “methods” section was poorly worded, but it gives the impression of sloppy work.
Discussion – explanations, rationalizations and excuses:
I’ll let you read the authors’ discussion for yourself, but I will include a few “highlights”:
“Our study design does not enable us to determine whether it is the vaccine per se, the exposure to Th [sic – thimerosal], or a combination of both, that is causing the observed effects [note: absolutely true – this is one of the main flaws of their design] None-the-less [sic], the developing brain is considered the most vulnerable organ to mercury exposure…”
After admitting that they couldn’t distinguish between the vaccine and the thimerosal – because of their own poor experimental design – they turn right around and say, in essence, “But we know it was the mercury…”
“Although the basis for the effect of birth weight is not known, it is plausible that lower birth weight infants are more susceptible to what may be a dose-dependent toxicity of Th [sic – thimerosal] or some other HB [sic – hepatitis B] vaccine component, such as aluminum.”
With absolutely no data to support this conjecture, the authors throw out aluminium as a potential vaccine-related toxin. It is important to note that there was no citation given to support this idea. It is telling that they do not consider what aspects of their study design might have led to these inexplicable results.
Conflict of interest statement:
In most papers, this is pretty dry and uninteresting and as I’m not a person to “dismiss out of hand“ a study because of potential conflicts of interest, I usually don’t give them a great deal of weight. [section removed]
[NOTE: as mentioned above, the neonatal assessments were performed by "L.A.H" - "Lisa A. Houser", so the conflict of interests statement is not incorrect, however much it may "whitewash" the previous actions by Drs. Wakefield and Scott.]
My conclusion:
This study raises more red flags than a Kremlin May Day parade in the old Soviet Union. It appears that control subjects were added post hoc and that unproductive reflexes were dropped from the data. One of the authors – the “anchor” author – has been implicated in research and ethical misconduct and is awaiting adjudication. Other authors have significant personal conflicts of interest.
But these are methodological problems. Apart from that, the study also has some serious flaws in its conclusions - even if we assume their methods produced good data.
First, there appears to be no attempt to correct for multiple comparisons. In fact - as mentioned above - there appears to have been an attempt to “prune” the data set. Since I doubt that they would have eliminated data that supported their point, I can only surmise that these data were “unproductive”.
Second – and most fatal for this study – is that there was not an increase in human infants who were late to suck, root, etc. following the introduction of neonatal hepatitis B vaccination in 1991. Given that the “uptake” of this vaccine at birth was close to (and often exceeded) 90%, an effect of this magnitude would have been noted. Nor is there a difference between the US – which has continued hepatitis B vaccination at birth – and the UK – which almost never gives the hepatitis B vaccine at birth – in developmental delay or autism prevalence.
Now, the authors – or their supporters – might argue that this delay would only be seen in a small number of human infants and so wouldn’t be seen against the background of the larger population. However, if this study could find a difference with only twenty subjects, it should be rampant in the general human population, if it is a real effect. Since the results of this study do not correlate to what we see in the human population - which has received the same exposure - it seems unlikely that it is relevant to human infants.
In short, this study was irrelevant from the moment it was published. At least, from a scientific perspective.
However, from the perspective of people facing the demolition of their argument that the MMR vaccine - with or without thimerosal - caused autism in their children, finding evidence - even spurious evidence - that a different vaccine might be to blame could be highly relevant. Could this be the explanation behind the study design and the curious collection of authors?
I guess we’ll know soon enough.
Prometheus
Filed under: Autism Science | 24 Comments »
Deductive Mis-reasoning
September 16th, 2009
At least once a day, I find myself confronting the aftermath of deductive reasoning gone wrong. Deductive reasoning is defined as “an argument (or reasoning) where the conclusion follows logically (or is a logical consequence) of its premises”. Many people - especially in ‘Blogland - are of the opinion that if their conclusions (or assertions) follow logically from their premises, that their conclusions must be true.
Unfortunately, that is not so.
Deductive reasoning (or deductive arguments) - according to the rules of Logic - can be either valid (if the conclusions are logical consequences of their premises) or invalid (if they are not). There is no “true”.
“Truth” (or “reality”, as I prefer to think of it) requires much more. For one, all of the premises of the argument must be correct (a place where many Internet writers of the conspiracy genre fail). Secondly - and most importantly - the conclusion must also be correct.
You see, there is usually more than one possible conclusion that can be logically drawn from a set of premises.
Let me use a nice neutral example to demonstrate this.
Surely the most famous champion of deductive reasoning is that creation of Arthur Conan Doyle, the great detective, Sherlock Holmes. In the opening pages of The Adventure of the Blue Carbuncle (1892), we find Sherlock Holmes making a number of startling conclusions about the owner of a hat [I will place the premise of each conclusions inside square brackets]:
“That the man was highly intellectual is of course obvious on the face of it [large hat size], and also that he was fairly well-to-do within the last three years [expensive hat], although he has now fallen upon evil days [wearing a hat three years out-of-style]. He had foresight [had a hat-securer installed on the hat], but has less now than formerly [elastic of the hat-securer is broken and not replaced], pointing to a moral retrogression, which, when taken with the decline of his fortunes, seems to indicate some evil influence, probably drink, at work upon him. This may account for the obvious fact that his wife has ceased to love him [the hat was dusty - not brushed. Presence of a wife inferred because the man was carrying a goose.].”
While these are all possible conclusions - thus, according to Logic, valid conclusions. There is, however, nothing to ensure that they are correct conclusions. Of course, they turn out to be correct in the story, but only because Sherlock Holmes had the author on his side. In real life, there is no such assurance. Here are some alternative conclusions that are equally valid and yet give a different picture of the owner.
[1] Large hat size: either a large gentleman (big people have big heads) or a large head size due to untreated (as it would be in that time) childhood hydrocephalus. The first would give no information about intellect, while the second would be consistent with reduced intellectual capacity. Of course, we now know that head size is no predictor of intellectual ability.
[2] Expensive hat: could have been purchased second-hand (which would also explain much of the other premises). Might have been a hand-me-down from a more wealthy relative or friend. Could have been stolen.
[3] Hat three years out-of-style: could have been purchased second-hand or given from a friend, relative, or generous stranger.
[4] Elastic hat-securer: see [2] and [3] above.
[5] Elastic of hat securer broken and not replaced: see [2] and [3] above.
[6] Dusty hat not brushed: too lazy to brush his own hat, slovenly, near-sighted and can’t see the dust. If we assume (as Holmes apparently did) that men of that time did not brush their own hats (even if they are noticeably dusty), he might have been a bachelor, widower or a transient visitor to London without his spouse. And even if we assume that men of that era did not cook geese, it does not mean that he was married. It could have been for a sister, the wife of a friend, his landlady, “significant other”, etc. who might cook a goose for him but not brush his hat.
So, with “alternative” conclusions that are consistent with the “data” at hand (i.e. “valid”), we draw a very different (or several very different) pictures of the hat’s errant owner.
This is a part of deductive reasoning that is not well-understood, apparently, by many people. There are usually several conclusions that can be drawn from any collection of data, but only one is correct.
On occasion, some of these conclusions can be eliminated by the simple fact that they are known (or reasonably presumed) to be false. A simple example of this is a GPS receiver, which can give you your position with information from only three satellites. Those who are adept at maths will realise that the position information from three satellites is the intersection of the surface of three spheres. Even under the best circumstances, this gives two points. Your GPS receiver resolves this apparent dilemma by rejecting the point that it presumes is nonsensical because it is either deep underground or out in space.
In most situations in science (and real life), however, the only way to resolve these multiple conclusions is to test them, through experimentation. There are generally two ways to do this: you can either directly test your conclusion (in the Sherlock Holmes example, this would be to find the hat’s owner) or you can gather more data and see if the new data contradict one or more of the possible conclusions.
Moving from fictional to real-life examples, let’s look at a few situations in which deductive reasoning has been misused.
Holmes et al, “Reduced levels of mercury in first baby haircuts of autistic children.” (Int. J. Toxicol., 2003 Jul-Aug;22(4):277-85.):
This is one of my favorite examples of poor reasoning (deductive or other), which is why I keep coming back to it. For those not intimately (or nauseatingly) familiar with this study, let me recap the “highlights”:
The authors studied hair saved from the “first baby haircut” of 94 autistic children and 45 age- and gender-matched non-autistic controls. The autistic group had a mean hair mercury of 0.47 ppm and the control group had a mean value of 3.63 ppm. They questioned the parents about various actual and potential mercury exposures during pregnancy and early childhood and came up with a “formula” that correlated these exposures to the control group’s hair mercury levels. This “formula” did not “predict” the hair mercury levels of the autistic group.
So, here are the “premises” that the authors used for their conclusion:
[1] Autistic children had far less mercury in their hair than the non-autistic controls.
[2] A formula that could take the “mercury exposures” (read the entire paper to see what this meant) of the control group and correlate it with their hair mercury levels did not predict the hair mercury levels of the autistic group.
And here is their conclusion:
“The lack of mercury in the hair of autistics may be due to a decrease in blood mercury levels feeding the hair follicles. This decrease is likely caused by the retention of the mercury inside the cells where it most likely causes its major biological damage.”
“Despite hair levels suggesting low exposure, these infants had measured exposures at least equal to a control population, suggesting that control infants were able to eliminate mercury more effectively.”
As it turns out, this conclusion was tested just about a year later. McDowell et al, in “Hair Mercury Levels in U.S. Children and Women of Childbearing Age: Reference Range Data from NHANES 1999–2000″ (Env. Health Perspect. 2004 Aug;112(11):1165-71), measured the hair mercury levels of 838 children ages 1 - 5 years (which includes the “first baby haircut” years). This much more extensive study found that the mean hair mercury level of these 838 children was 0.22 ppm, thus wiping out the first premise of Holmes et al’s conclusion.
However, even if we grant Holmes et al their obviously flawed premise (in which their “control” group had hair mercury levels which averaged over sixteen times the mean hair mercury of 838 children in the NHANES survey, there are “alternative” conclusions that do not require inventing “poor excretion”.
The first of these, although it seems obvious, is that - despite their attempts to quantify mercury exposure many years after the fact - the autistic children were actually exposed to less mercury than the control group. Given the known problems with getting accurate dietary and even medical data years after the fact, this seems a reasonable conclusion.
A second obvious conclusion is that the higher mercury exposure of the control group actually prevented autism. This seems a bit counter-intuitive, but it is logically consistent with the laboratory data reported in Holmes et al.
A third conclusion presents itself now that we know the control group in Holmes et al had hair mercury levels far out of the “normal” range (the NHANES study showed the 95th percentile to be 0.64 ppm). This conclusion is that either the control group had a massive and undiscovered exposure to mercury in their early years or the hair mercury analysis of this group was “botched” in the lab. I hope, for these children’s sake, that it was the latter.
In this example, not only did the authors fail to consider most of the alternative conclusions that were consistent with their premises (”data”), it turns out that one of their premises - the major one - was apparently incorrect.
James et al, “Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.” (FASEB J., 2009 Aug;23(8):2374-83)
This study is a much “cleaner” example, in that there is no reason to suspect that its data is erroneous and it appears to be a well-designed study.
In this study, the authors examined cultured lymphoblastoid (precursors to lyphocytes) cells from ten autistic children (mean age 7.8 years) and ten control adults (mean age 27.7 years). They found that the cells from the autistic children had lower whole cell and mitochondrial reduced glutathione (GSH) and higher oxidised glutathione (GSSG) than the cells from the control adults.
They also found that the cells from autistic children were more sensitive to oxidative stress from thimerosal and nitric oxide (NO).
In their conclusions, the authors state:
“A potential role of subclinical mitochondrial dysfunction and altered redox homeostasis in a subset of children with autism has been previously proposed. Within the limitations of an in vitro cell model, the baseline differences in intracellular and mitochondrial glutathione redox status in autism and control LCLs cultured under identical conditions would support this possibility.” [emphasis added]
“These potentially vulnerable subpopulations need to be identified and evaluated independently because large population epidemiologic studies do not have the sensitivity to detect minor high-risk subpopulations.” [emphasis added]
As I’ve stated above, I have no issue with the methods of this study. But the parts of their conclusions that I’ve highlighted are glaringly invalid (i.e. they do not logically flow from their premises/data).
Some of you have probably already figured it out, but let me give the rest of you a hint: they studied cells from only ten autistic children.
If this were a “subpopulation” problem, a problem seen in only a “subset” of autistic children who were part of a “minor high-risk subpopulation”, why did they see it so clearly in cells from only ten children?
The only criteria used for selecting the autistic subjects was that they had to have ”at least one affected male sibling” - so they were looking only at familial autism. Even so, it is remarkable that they were able to find this “minor high-risk subpopulation” with so few subjects. This would suggest that having two autistic children is a marker for redox imbalance.
If we conclude - as the authors apparently did - that having two autistic children is a marker of redox imbalance, then it should be a relatively simple matter to test this conclusion, since the “minor high-risk subpopulation” is easily identified. I eagerly await the results of the study that looks into this.
And even if we accept the implication that all strongly familial autism is accompanied by this redox imbalance, there is still nothing in this study that shows causation. It is equally valid to conclude - from these data - that strongly familial autism is accompanied by a redox imbalance. There is nothing in this study to show causation.
In fact, since thimerosal (the only exogenous oxidant tested) was removed from childhood vaccines at a time roughly equal to the mean age of the study subjects, at least half of them had no significant exposure to thimerosal.
So, we see that we have to be very careful about blindly accepting the conclusions of scientific papers - even from studies that are otherwise well-designed and well-executed. We are fortunate that scientific papers generally include enough detail for us to determine if the data support the conclusions and if the conclusions reached by the authors are the only valid conclusions.
And if this is true for scientific papers, just imagine what is happening on ‘blogs, websites and the like.
Bottom line: ask people to “show their work”. If they won’t……well, use caution.
Prometheus
Filed under: Autism Science, Critical Thinking, Help for the bewildered | 16 Comments »