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Anthony Cox published in PJ Online

11 Feb

Our very own Anthony Cox was published today in PJ Online (gateway to the world of pharmacy and medicines) concerning the MMR saga. I’ll copy and paste a key paragraph then urge you to go read the whole piece which is an excellent summation of events thus far.

In US court testimony in 2007, Chadwick stated that he had tested all the samples from Wakefield’s ASD children and found no MVV present. Wakefield was made aware of this before the publication of the 1998 paper, but saw fit not to draw attention to this negative finding that undermined his hypothesis.

Coming soon, the DSM-V. No more “PDD-NOS”, no more “Asperger”

11 Feb

Yes, a new version of the Diagnostic and Statistical Manual (DSM) is in the works. You’ve probably heard “DSM-IV” or read it a number of times. It is the manual used to describe the various “mental disorders” and the criteria for diagnosing them. (Pervasive Developmental Disorders or PDD’s are described there. These include Autistic Disorder, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Asperger Syndrome, Rett Syndrome and Childhood disintegrative disorder. If the proposed changes go into place, all that will be left is Autism Spectrum Disorder.

It isn’t that people with diagnoses of Asperger or PDD-NOS will no longer will no longer be recognized as having a diagnosis. It is just that the diagnosis name will be replaced with Autism Spectrum Disorder.

Here is are the proposed DSM-V criteria for Autism Spectrum Disorder (299.00)

Autism Spectrum Disorder

Must meet criteria 1, 2, and 3:

1. Clinically significant, persistent deficits in social communication and interactions, as manifest by all of the following:

a. Marked deficits in nonverbal and verbal communication used for social interaction:

b. Lack of social reciprocity;

c. Failure to develop and maintain peer relationships appropriate to developmental level

2. Restricted, repetitive patterns of behavior, interests, and activities, as manifested by at least TWO of the following:

a. Stereotyped motor or verbal behaviors, or unusual sensory behaviors

b. Excessive adherence to routines and ritualized patterns of behavior

c. Restricted, fixated interests

3. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)

Compare this to the DSM-IV criteria

299.00 Autistic Disorder

1. A total of six (or more) items from (1), (2), and (3), with at least two from (1), and one each from (2) and (3):
1. Qualitative impairment in social interaction, as manifested by at least two of the following:
1. marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction.
2. failure to develop peer relationships appropriate to developmental level
3. a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest)
4. lack of social or emotional reciprocity
2. Qualitative impairments in communication as manifested by at least one of the following:
1. delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime)
2. in individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others
3. stereotyped and repetitive use of language or idiosyncratic language
4. lack of varied spontaneous make-believe play or social imitative play appropriate to developmental level
3. Restricted, repetitive, and stereotyped patterns of behavior, interests, and activities, as manifested by at least of one of the following:
1. encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus
2. apparently inflexible adherence to specific, nonfunctional routines or rituals
3. stereotyped and repetitive motor mannerisms (e.g. hand or finger flapping or twisting, or complex whole body movements)
4. persistent preoccupation with parts of objects
2. Delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years: (1) social interaction, (2) language as used in social communication, or (3) symbolic or imaginative play.
3. The disturbance is not better accounted for by Rett’s disorder or childhood disintegrative disorder.

For a good discussion, there is an op-ed piece in the New York Times by Prof. Roy Richard Grinker. Prof. Grinker discusses about how the separate category of Asperger Syndrome really is not necessary in today’s culture. The reduced stigma attached to Autism makes it less helpful to have a separate name for “less severe” autism.

Professor Grinker was also interviewed for the United States’ National Public Radio. You can read or listen on their site.

Autistic Disorder, PDD-NOS, Asperger Syndrome and Childhood Disintigrative Disorder will all be a part of the new “Autism Spectrum Disorder”. Rett Syndrome will not be in the DSM-V at all.

One thing this will change is access to services–or possibly. For example, the State of California has “autism” as an eligibility category in the Department of Developmental Disabilities. This was put in place before the DSM-IV and the diagnosis of Asperger Syndrome was used. The state has interpreted the law to mean that only Autistic Disorder is a qualifying diagnosis, denying people with PDD-NOS and Asperger diagnoses unless they meet the criteria for the “other category”. This has put pressure to diagnose “Autistic Disorder” over PDD or AS.

Given the current budget crisis in the State of California, it isn’t as though having a diagnosis of “autism” is a key to great services anyway.

That all said, it will be interesting to hear the discussion of this change. One point that is interesting is the removal of the age 3 limit. Before, there had to be onset of symptoms before age 3. Now it is a more general statement: “Symptoms must be present in early childhood”. I find it interesting that the lack of imaginary play statement is gone as well.

The DSM is not a checklist. In the end, it will be the diagnostic instruments like the ADOS that will determine whether someone qualifies for a diagnosis. I wonder how they will modify these instruments? The “imaginary play” requirement seems to be in the ADOS as it stands now, with the birthday party section for example.

Maternal age affects autism development?

10 Feb

A new study that looked at a large birth cohort (almost 5 million participants) over a 10 year period has announced that maternal age is an indicator of developing autism with an approximately 50% higher risk for a woman in her forties than a woman in her twenties.

The researchers looked at the records for all births in California between Jan 1990 and Dec 1999. Cases of autism were identified from this cohort using the records from the Early Start Report (ESR) for children under three, and the Client Development and Evaluation Report (CDER) for children over three.

A diagnosis of autism was defined as either positive for Developmental Disabilities on the ESR, or an autism level of one a CDER record/ICD code for autistic disorder. After excluding children from multiple births and those with missing data there were 12,159 cases and 4,935,776 controls.

Thats an interesting autism rate of 0.2% which might indicate more than maternal age that ESR or CDER is not that good at catching autism diagnoses as its a very low rate compared to the US national 1%.

This paper also lacks strength when looking at confounding factors – admittedly a tricky proposition as we don’t know what causes autism – but it may be of interest that the confounding factors that they _did_ account for were mainly ethnocentric i.e. race, gender etc and that they found that yep – whites were mainly very well represented. It seems very likely therefore that of possibly more interest that maternal age might be that not enough efforts are being made by local authorities to go into non-white enclaves.

Stem Cell Therapy for Autism

10 Feb

There are many unproven therapies being used by alternative medicine practitioners on autistic kids. One newer “therapy” is the use of stem cells.

I have yet to see even a good explanation of why stem cells should work. Not even a fully thought out bad reason. And, yet, kids are being “treated” with stem cells.

For those who would like a rundown of stem cells, their use and the potential problems, I refer you to Promtheus’ A Photon In The Darkness blog and his post, Stem Cell Therapy for Autism.

Not to steal his thunder, but here is the part that I am having trouble getting out of my mind. A child was given multiple stem cell “treatments”. Later he developed recurring headaches. On testing…well, Prometheus says it:

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.

Many alternative medical therapies appear to be basically harmless. Give a kid some extra vitamin, or change his/her diet. Stem cell therapy does not fall into that category. When a risk/benefit calculation is done, what can you say but there is significant risk and no discernible benefit.

Wakefield, O’Leary and Bustin

4 Feb

Below is an old post from 2007 when the Omnibus hearings were in full swing. It goes through the testimony of Professor Stephen Bustin and why it was so deadly to the MMR hypothesis. I thought now might be an ideal time to republish it.

On Day 8 of the Autism Omnibus proceedings, the MMR section of the hypothesis under examination (that thiomersal and MMR together cause autism) was examined. Just to briefly generalise about the MMR hypothesis –

It was hypothesised that measles virus (MV) from the MMR was travelling from the injection site, to the gut and then to the brain where it either a) causes autism or b) in conjunction with thiomersal causes autism. Wakefield claims to have found MV in the gut of several kids. Krigsman claimed to have replicated this work. They both used the lab of one Professor John O’Leary (Unigenetics IIRC) in Ireland.

So, on Day 8 of these proceedings Stephen Bustin came to the stand. Bustin is possibly _the_ world expert on the techniques used in the O’Leary lab that he claimed led to identifying MV in autistic kids gut and brain. The technique is called PCR. Not only does Bustin use PCR every day, he has 14 papers in the peer reviewed literature on PCR, over 8 book chapters and is personally the author of the _A to Z of Quantitative PCR._ which is considered ‘the bible’ of PCR. One of his papers has been cited over 1,000 times. Another has been cited over 500 times. He both organises and speaks at international PCR conferences (1934 – 37).

Basically, when it comes to PCR – this is the guy.

The first part of Bustin’s testimony concentrated on an explanation of PCR techniques and how these techniques were employed in a key study relied upon the week previous to make the MMR/Cedillo case: Uhlmann 2002. This paper describes the _exact process that Unigentics lab used to carry out their PCR work_ .

This is a mind bogglingly techie area so I’m going to try and stick to laypersons terms. Basically, the Uhlmann study is badly flawed. The key issues related to controls. Uhlmann (and a subsequent, as yet unpublished Walker poster presentation) didn’t use any.

a positive control is an essential control that tells you whether your assay is working, so what you would do is you would take the target that you’re interested in detecting and put it into a test tube and use your assay to detect it. If you don’t detect it, you know there’s a problem with your assay because it’s a positive control. If you do detect it, you know your assay is working. If you do this consistently each time, you know how efficient your assay is from day to day.

The positive control is simply something that tells you that your assay is okay.

Q And a negative control?
A A negative control is something very crucial. There you leave out your target, so if you don’t detect it then that means that there’s no amplification, which is what you want. If you do detect a positive in a negative control then you know there’s a problem with your assay because it should not be there, and you always get suspicious of any assay that gives you a positive result in a negative control.

So, back to Uhlmann:

Q And did Uhlmann provide the information necessary to establish whether these controls were working as expected?
A No. One of the surprising aspects of this paper is they give you very little information about how the assay was performed, about what the results actually were, and it really does not let you evaluate at all how reliable and consistent the results are.

Q Is there any discussion in Uhlmann about contamination?
A No.

Q Is this important?
A It is essential because obviously if you are trying to detect a very low copy number target and there is contamination around, and if you do not know whether there’s contamination around, then you can’t rely on your assay.

……

Q Now, did Uhlmann discuss how the RNA was handled?
A No. As I think I said one of the things about this paper is that it’s fairly unique in my experience, and it’s given no information at all about what actually was done. It actually tells you in outline what they did, where they got their samples from and that they prepared RNA, but it gives you no information whatsoever about, for example, the quality of the RNA the quantity of the RNA and how the different RNAs were extracted from different samples which they refer to.

Without being sure of how RNA is handled, it is impossible to rule out contaminants. i.e. that the samples are contaminated. And there’s more:

Q Did you also identify a mismatch between the measles virus sequences listed in the paper and the probes?
A Yes. This is, again, well, it suggests that there’s a problem with the probe design.

Q Now, regarding consistency and reproducibility did Uhlmann provide any data regarding amplification sensitivity or efficiency?
A No. I need to come back to what I’ve been saying several times now. There’s this lack of information that doesn’t allow you to evaluate this paper properly in terms of its validity.

And specifically regarding the Walker poster presentation:

….Now, as I tried to point out today I think virtually every expert in this case has referred to controls are essential. You always want controls of your samples. There’s no controls on this. So even though this is a poster presentation at the very least there should be a negative control on there to show that the PCR in the negative control hasn’t worked.

We don’t have that information. So this immediately invalidates these results because we can’t now say whether these are genuine or not because there’s no negative control there. So that’s a real problem….

Q Unless these issues are resolved would you have confidence at least in what’s been presented from the Walker lab?
A I can’t have any confidence because there’s actually no results I can evaluate without referring to a negative or a positive control, and these don’t give them to me.

So basically, Mr PCR – the guy who literally wrote the book on PCR – thinks these two things – the Uhlmann paper and the Walker poster presentation – are essentially useless.

Lets also not forget that these two items describe the exact methodology that Unigentics – O’Leary’s lab – used to state that Wakefields/Krigsmans and a multitude of private cases had MV in their samples.

Oh yeah – and as for the old crapola about the two clinical studies done thus far not repudiating Wakefield et al because the look at blood, not gut, Bustin states emphatically:

this is not an assay that is at its limits so this should be easily detectible, and it also means that if you’ve got that much measles virus in a gut sample it probably is in other cells as well and you should be able to detect it, for example, in blood.

In blood.

Turning to Unigenetics itself, as part of the failed UK litigation against MMR, Bustin was asked to look at the lab and samples that the Unigentics team had worked on. For this work he put in an astonishing 1,500 hours of work.

Now, Professor O’Leary’s own controls tell us that this should have been shifted upwards because this is much poorer quality RNA. The evidence from his own data is completely clear. There’s no such shift. This must mean that whatever this is is a contaminant that has been introduced after the sample has been formalin-fixed.

So by definition this cannot be part of the original biopsy because if it had been it will have shifted upwards.

Ouch. But the next one is a body blow to the entire MMR hypothesis.

…if you have a reference gene in that sample that is a cellular reference gene you should detect it if the RNA is of good quality.

If you don’t detect it there’s something wrong with the RNA. As Professor O’Leary’s SOP states, if we can’t detect the GAPDH we shouldn’t use the sample for analysis, which makes perfect sense.

Now, it happens that Professor O’Leary did use those samples for his analysis, and that’s why I was able to then hopefully identify what the contaminant is.

To summarise: O’Leary’s RNA was poor quality. There is no reference gene. There is something wrong with the RNA. O’Learys lab SOP (Standard Operating Procedure) states that in the events of this happening, they shouldn’t use the sample for analysis. But they did use it. They used contaminated RNA for their analysis. And Bustin has identified exactly what the contaminant was.

But first, what is _definitely not_ ?

If you detect a target that is apparently measles virus in the absence of an RT [like this one] step by definition it can’t be measles virus because it has to be DNA [measles virus does not exist as a DNA molecule]. It’s a very simple concept. At least it is to me. It’s not to everyone else.

Whatever it is that O’Learys lab is picking up in their lab tests, it cannot possibly be Measles virus. No RT step was taken:

What I immediately observed was that they had forgotten to do the RT step

No RT step means it’s DNA. Measles virus does not exist as a DNA molecule. That’s simple medical fact. Bustin later summed up:

So all of this evidence suggests very, very strongly that what they are detecting is DNA and not RNA. Because measles virus doesn’t exist as a DNA molecule in nature, they cannot be detecting measles virus RNA. They are detecting a contaminant. All of the additional evidence, from the nonreproducibility by Professor Cotter of the same samples that Unigenetics analyzed to the analysis of the data where there are discordant positives, where the negatives came up positive, suggests very, very strongly to me that there is a lot of contamination in the laboratory, which is not unusual, but they have not handled it very well in how they have troubleshot their problems.

So I have very little doubt that what they are detecting is a DNA contaminant and not measles virus, and I do not believe there is any measles virus in any of the cases they have looked at.

And just as an added kick in the teeth:

Q Now, we know that cerebral spinal fluid samples were sent from Dr. Bradstreet to Unigenetics for testing. Do the same concerns you’ve outlined here apply to that testing?
A Yes. Exactly the same concerns would apply to that.

This testimony exposes the MMR hypothesis as totally dead in the water. What a waste of time, money and health.

Elsewhere

Arthur Allen in the Huffington Post
Autism Diva

More on autism “clusters”

4 Feb

There are regions of California where the autism “rate” is much higher than in other regions. If you are a regular reader of this blog, you are likely thinking “repeat!” Yes, between Kev and myself and even the Evil Possum himself, David N. Brown, we have about 10 posts about the GMC ruling on Andrew Wakefield and the retraction of his article in The Lancet. Now another “autism cluster” post?

Only a month ago I blogged “Autism Clusters Found: areas with high incidence of autistic children“, discussing a paper by Dr. Hertz-Picciotto at the U.C. Davis MIND Institute. Well, it turns out that another “cluster” paper has been published. This article, The spatial structure of autism in California 1993-2001, is by Prof. Bearman’s group at Columbia. This is the same group that recently published Diagnostic change and the increased prevalence of autism

Here’s the abstract:

The spatial structure of autism in California, 1993-2001.

Mazumdar S, King M, Liu KY, Zerubavel N, Bearman P.

Institute for Social and Economic Research and Policy Columbia University, New York, NY, USA.

This article identifies significant high-risk clusters of autism based on residence at birth in California for children born from 1993 to 2001. These clusters are geographically stable. Children born in a primary cluster are at four times greater risk for autism than children living in other parts of the state. This is comparable to the difference between males and females and twice the risk estimated for maternal age over 40. In every year roughly 3% of the new caseload of autism in California arises from the primary cluster we identify-a small zone 20km by 50km. We identify a set of secondary clusters that support the existence of the primary clusters. The identification of robust spatial clusters indicates that autism does not arise from a global treatment and indicates that important drivers of increased autism prevalence are located at the local level

They used data from the California Department of Developmental Services (CDDS). This dataset has been discussed a lot online. While the work of Dr. Bearman’s group and Dr. Hertz-Picciotto’s group are both much more rigorous than the simple comparisons done by myself and others, there are severe limitations in using CDDS data. The CDDS does not make an effort to seek out all autistics, for one thing. There are variations by Regional Center in identification and services for disabled Californians.

That said, Prof. Bearman’s group found a large “cluster”. If a child was born in this region, he/she is about 4 times more likely to be listed by the CDDS with the label of autism than if he/she were born in the rest of California.

The cluster is in the Los Angeles area. (map was taken from the Wall Street Journal’s story, L.A. Confidential: Seeking Reasons for Autism’s Rise)

Prof. Bearman’s group checked that the cluster was stable over time and found that there was a region with the high administrative prevalence existed for 5 or more years. That is one good check that this is a “real” cluster and not a statistical artifact.

The Wall Street Journal quotes Prof. Bearman:

Dr. Bearman says he believes social influences are the leading cause for the high autism rates in Los Angeles, although the researchers continue to examine environmental issues.

Other studies have shown that older parents run a greater risk of having an autistic child. But when the Columbia researchers adjusted the Los Angeles cluster to factor out parental age, the higher levels remained. Dr. Bearman says he believes the high levels will also remain after the data are adjusted for education levels, socio-economic status and other demographic characteristics in future studies.

You may recall that the MIND Institute study found multiple “clusters”, using different criteria.

There is a cluster roughly centered on Hollywood in those maps, consistent with the newer Columbia study. (as an aside, the closeup map from the MIND Institute press release doesn’t look like the same region to me.)

It seems reasonable to assume that both groups were looking for clusters in a search for a possible “hot spot” of some environmental trigger for autism. Instead, Bearman’s group indicates “social issues” and Hertz-Picciotto’s group found parental education and proximity to autism treatment centers were linked to the “clusters”.

Both groups are to be commended, in my view. They are looking for some answers on causation. They are working with data that are much less than high quality, and they are dealing with shifting awareness and societal influences which could cloud any trends that may or may not exist.

The new IACC Strategic Plan is online

4 Feb

The Interagency Autism Coordinating Committee (IACC) has posted the revised “Strategic Plan“. This is the document which is supposed to guide US Government funded autism research.

The Strategic Plan is written from a parent’s perspective. It is divided into 7 questions to be answered. Below I list the parts I think are the “meat” of the Plan–the proposed projects with estimated budgets.

In a very quick skim through the budget, I get 7 projects on environmental causes or gene-environment causes, with budgets totaling nearly $200M. Keep that in mind when people say there is no “environmental” research in the Plan.

There are a lot of new projects. My quick sum gives about $64M in projects for question 6 “What Does the Future Hold, Particularly for Adults?” I This is, to me, the most important part of the Plan.

Question 1: When Should I Be Concerned?

Short-Term Objectives

1. Develop, with existing tools, at least one efficient diagnostic instrument (e.g., briefer, less time intensive) that is valid in diverse populations for use in large-scale studies by 2011. IACC Recommended Budget: $5,300,000 over 2 years.
2. Validate and improve the sensitivity and specificity of new or existing screening and diagnostic tools, including comparison of general developmental screening versus autism-specific screening tools, in both high risk and population-based samples through studies of the following community populations that are diverse in terms of age, socio-economic status, race, ethnicity, characteristics of ASD, and general level of functioning by 2012. IACC Recommended Budget: $5,400,000 over 3 years.
3. New objective
Conduct at least three studies to identify reasons for the health disparities in accessing early screening and diagnosis services by 2012. IACC Recommended Budget: $2,000,000 over 2 years.
4. New objective
Conduct at least two studies to understand the impact of early diagnosis on choice of intervention and outcomes by 2015. IACC Recommended Budget: $6,000,000 over 5 years.

Long-Term Objectives

1. Identify behavioral and biological markers that separately, or in combination, accurately identify, before age 2, one or more subtypes of children at risk for developing ASD by 2014. IACC Recommended Budget: $33,300,000 over 5 years.
2. Develop at least five measures of behavioral and/or biological heterogeneity in children or adults with ASD, beyond variation in intellectual disability, that clearly relate to etiology and risk, treatment response and/or outcome by 2015. IACC Recommended Budget: $71,100,000 over 5 years.
3. Identify and develop measures to assess at least three “continuous dimensions” (i.e., social reciprocity, communication disorders, and repetitive/restrictive behaviors) of ASD symptoms and severity that can be used by practitioners and/or families to assess response to intervention for people with ASD across the lifespan by 2016. IACC Recommended Budget: $18,500,000 over 5 years.

Question 2: How Can I Understand What Is Happening?

Short-Term Objectives

1. Support at least four research projects to identify mechanisms of metabolic and/or immune system interactions with the central nervous system that may underlie the development of ASD during prenatal-postnatal life by 2010. IACC Recommended Budget: $9,800,000 over 4 years.
2. Launch three studies that specifically focus on the neurodevelopment of females with ASD, spanning basic to clinical research on sex differences by 2011. IACC Recommended Budget: $8,900,000 over 5 years.
3. Identify ways to increase awareness among the autism spectrum community of the potential value of brain and tissue donation to further basic research by 2011. IACC Recommended Budget: $1,400,000 over 2 years.
4. New objective
Launch three studies that target improved understanding of the underlying biological pathways of genetic conditions related to autism (e.g. Fragile X, Rett syndrome, tuberous sclerosis complex) and how these conditions inform risk assessment and individualized intervention by 2012. IACC Recommended Budget: $9,000,000 over 5 years.
5. New objective
Launch three studies that target the underlying biological mechanisms of co-occurring conditions with autism including seizures/epilepsy, sleep disorders and familial autoimmune disorders by 2012. IACC Recommended Budget: $9,000,000 over 5 years.
6. New objective
Launch two studies that focus on prospective characterization of children with reported regression, to investigate potential risk factors by 2012. IACC Recommended Budget: $4,500,000 over 5 years.
7. New objective
Support five studies that associate specific genotypes with functional or structural phenotypes, including behavioral and medical phenotypes (e.g., nonverbal individuals with ASD and those with cognitive impairments) by 2015. IACC Recommended Budget: $22,600,000 over 5 years.

Long-Term Objectives

1. Complete a large-scale, multi-disciplinary, collaborative project that longitudinally and comprehensively examines how the biological, clinical, and developmental profiles of individuals, with a special emphasis on females, youths, and adults with ASD, change over time as compared to typically developing people by 2020. IACC Recommended Budget: $126,200,000 over 12 years.
2. New objective
Launch at least three studies which evaluate the applicability of ASD phenotype and/or biological signature findings for performing diagnosis, risk assessment, or clinical intervention by 2015. IACC Recommended Budget: $7,200,000 over 5 years.

Question 3: What Caused This To Happen And Can This Be Prevented?

Short-Term Objectives

1. Coordinate and implement the inclusion of approximately 20,000 subjects for genome-wide association studies, as well as a sample of 1,200 for sequencing studies to examine more than 50 candidate genes by 2011. Studies should investigate factors contributing to phenotypic variation across individuals that share an identified genetic variant and stratify subjects according to behavioral, cognitive, and clinical features. IACC Recommended Budget: $43,700,000 over 4 years.
2. Within the highest priority categories of exposures for ASD, identify and standardize at least three measures for identifying markers of environmental exposure in biospecimens by 2011. IACC Recommended Budget: $3,500,000 over 3 years.
3. Initiate efforts to expand existing large case-control and other studies to enhance capabilities for targeted gene – environment research by 2011. IACC Recommended Budget: $27,800,000 over 5 years.
4. Enhance existing case-control studies to enroll racially and ethnically diverse populations affected by ASD by 2011. IACC Recommended Budget: $3,300,000 over 5 years.
5. New objective
Support at least two studies to determine if there are subpopulations that are more susceptible to environmental exposures (e.g., immune challenges related to infections, vaccinations, or underlying autoimmune problems) by 2012. IACC Recommended Budget: $8,000,000 over 2 years.
6. New objective
Initiate studies on at least 10 environmental factors identified in the recommendations from the 2007 IOM report “Autism and the Environment: Challenges and Opportunities for Research” as potential causes of ASD by 2012. Estimated cost $56,000,000 over 2 years.

Long-Term Objectives

1. Conduct a multi-site study of the subsequent pregnancies of 1,000 women with a child with ASD to assess the impact of environmental factors in a period most relevant to the progression of ASD by 2014. IACC Recommended Budget: $11,100,000 over 5 years.
2. Identify genetic risk factors in at least 50% of people with ASD by 2014. IACC Recommended Budget: $33,900,000 over 6 years.
3. Determine the effect of at least five environmental factors on the risk for subtypes of ASD in the pre- and early postnatal period of development by 2015. IACC Recommended Budget: $25,100,000 over 7 years.
4. Support ancillary studies within one or more large-scale, population-based surveillance and epidemiological studies, including U.S. populations, to collect data on environmental factors during preconception, and during prenatal and early postnatal development, as well as genetic data, that could be pooled (as needed), to analyze targets for potential gene/environment interactions by 2015. IACC Recommended Budget: $44,400,000 over 5 years.

Question 4: Which Treatments and Interventions will Help?

Short-Term Objectives

1. Support at least three randomized controlled trials that address co-occurring medical conditions associated with ASD by 2010. IACC Recommended Budget: $13,400,000 over 3 years.
2. Standardize and validate at least 20 model systems (e.g. cellular and/or animal) that replicate features of ASD and will allow identification of specific molecular targets or neural circuits amenable to existing or new interventions by 2012. IACC Recommended Budget: $75,000,000 over 5 years.
3. Test safety and efficacy of at least five widely used interventions (e.g., nutrition, medications, assisted technologies, sensory integration, medical procedures) that have not been rigorously studied for use in ASD by 2012. IACC Recommended Budget: $27,800,000 over 5 years.
4. Complete two multi-site randomized controlled trials of comprehensive early intervention that address core symptoms, family functioning and community involvement by 2013. IACC Recommended Budget: $16,700,000 over 5 years.
5. New objective
Convene a workshop to advance the understanding of clinical subtypes and treatment personalization (i.e. what are the core symptoms to target for treatment studies) by 2011. IACC Recommended Budget: $50,000.
6. New objective
Launch five randomized controlled trials of interventions including biological signatures and other measures to predict response, and monitor quality of life and functional outcomes, in each of the following groups:

* Five trials in infants and toddlers by 2013. IACC Recommended Budget: $30,000,000 over 5 years.
* Three randomized controlled trials of interventions for school-aged children and/or adolescents by 2013. IACC Recommended Budget: $18,000,000 over 5 years.
* Three trials for adults by 2014.IACC Recommended Budget: $18,000,000 over 5 years.

Long-Term Objectives

1. Complete at least three randomized controlled trials on medications targeting core symptoms in people with ASD of all ages by 2014. IACC Recommended Budget: $22,200,000 over 5 years.
2. Develop interventions for siblings of people with ASD with the goal of reducing risk recurrence by at least 30% by 2014. IACC Recommended Budget: $6,700,000 over 5 years.
3. New objective
Conduct at least one study to evaluate the safety and effectiveness of medications commonly used in the treatment of co-occurring conditions or specific behavioral issues in people with ASD by 2015. IACC Recommended Budget: $10,000,000 over 5 years.

Question 5: Where Can I Turn for Services?

Short-Term Objectives

1. Support two studies that assess how variations and access to services affect family functioning in diverse populations, including underserved populations, by 2012. IACC Recommended Budget: $1,000,000 over 3 years.
2. New objective
Conduct one study to examine how self-directed community-based services and supports impact children, youth, and adults with ASD across the spectrum by 2014. IACC Recommended Budget: $6,000,000 over 3 years.
3. New objective
Implement and evaluate two models of policy and practice-level coordination among state and local agencies to provide integrated and comprehensive community-based supports and services that enhance access to services and supports, self-determination, economic self-sufficiency, and quality of life for people with ASD across the spectrum and their families, with at least one project aimed at the needs of transitioning youth by 2015. IACC Recommended Budget: $10,000,000 over 5 years.

Long-Term Objectives

1. Test four methods to improve dissemination, implementation, and sustainability of evidence-based interventions, services, and supports in diverse community settings by 2013. IACC Recommended Budget: $7,000,000 over 5 years.
2. Test the efficacy and cost-effectiveness of at least four evidence-based services and supports for people with ASD across the spectrum and of all ages living in community settings by 2015. IACC Recommended Budget: $16,700,000 over 5 years.
3. New objective
Evaluate new and existing pre-service and in-service training to increaseskill levels in service providers, including direct support workers, parents and legal guardians, education staff, and public service workers to benefit the spectrum of people with ASD and promote interdisciplinary practice by 2015. IACC Recommended Budget: $8,000,000 over 5 years.

Question 6: What Does the Future Hold, Particularly for Adults?

Short-Term Objectives

1. New objective
Launch at least two studies to assess and characterize variation in the quality of life for adults on the ASD spectrum as it relates to characteristics of the service delivery system (e.g., safety, integrated employment, post-secondary educational opportunities, community inclusion, self-determination, relationships, and access to health services and community-based services) and determine best practices by 2012. IACC Recommended Budget: $5,000,000 over 3 years.
2. New objective
Evaluate at least one model, at the state and local level, in which existing programs to assist people with disabilities (e.g., Social Security Administration, Rehabilitation Services Administration) meet the needs of transitioning youth and adults with ASD by 2013. IACC Recommended Budget: $5,000,000 over 3 years.
3. New objective
Develop one method to identify adults across the ASD spectrum who may not be diagnosed, or are misdiagnosed, to support service linkage, better understand prevalence, track outcomes, with consideration of ethical issues (insurance, employment, stigma) by 2015. IACC Recommended Budget: $8,400,000 over 5 years.
4. New objective
Conduct at least one study to measure and improve the quality of life-long supports being delivered in community settings to adults across the spectrum with ASD through provision of specialized training for direct care staff, parents, and legal guardians, including assessment and development of ASD-specific training, if necessary, by 2015. IACC Recommended Budget: $7,500,000 over 5 years.

Long-Term Objectives

1. New objective
Develop at least two individualized community-based interventions that improve quality of life or health outcomes for the spectrum of adults with ASD by 2015. IACC Recommended Budget: $12,900,000 over 5 years.
2. New objective
Conduct one study that builds on carefully characterized cohorts of children and youth with ASD to determine how interventions, services, and supports delivered during childhood impact adult health and quality of life outcomes by 2015. IACC Recommended Budget: $5,000,000 over 5 years.
3. New objective
Conduct comparative effectiveness research that includes a cost-effectiveness component to examine community-based interventions, services and supports to improve health outcomes and quality of life for adults on the ASD spectrum over age 21 by 2018. IACC Recommended Budget: $6,000,000 over 5 years.
4. New objective
Conduct implementation research to test the results from comparative effectiveness research in real-world settings including a cost-effectiveness component to improve health outcomes and quality of life for adults on the ASD spectrum over age 21 by 2023. IACC Recommended Budget: $4,000,000 over 5 years.

Question 7: What other Infrastructure and Surveillance Needs Must be Met?

Short-Term and Long-Term Objectives

1. Conduct a needs assessment to determine how to merge or link administrative and/or surveillance databases that allow for tracking the involvement of people living with ASD in healthcare, education and social services by 2009 . IACC Recommended Budget: $520,000 over 1 year.
2. Conduct an annual “State of the States” assessment of existing state programs and supports for people and families living with ASD by 2009. IACC Recommended Budget: $300,000 each year.
3. Develop and have available to the research community means by which to merge or link databases that allow for tracking the involvement of people in ASD research by 2010. IACC Recommended Budget: $1,300,000 over 2 years.
4. Establish and maintain an international network of biobanks for the collection of brain, fibroblasts for pluripotent stem cells, and other tissue or biological material, by acquisition sites that use standardized protocols for phenotyping, collection, and regulated distribution of limited samples by 2011. This includes developing fibroblast repositories to produce pluripotent stem cells. Protocols should be put into place to expand the capacities of ongoing large-scale children’s studies to collect and store additional biomaterials, promoting detection of biological signatures. IACC Recommended Budget for establishing biobanks by 2011: $10,500,000 over 2 years. IACC Recommended Budget for maintaining biobanks: $22,200,000 over 5 years.
5. New objective
Begin development of a web-based toolbox to assist researchers in effectively and responsibly disseminating their finding to the community, including people with ASD, their families, and health practitioners by 2011. IACC Recommended Budget: $400,000 over 2 years.
6. New objective
Create funding mechanisms that encourage rapid replication studies of novel or critical findings by 2011.
7. New objective
Develop a web-based tool which provides population estimates of ASD prevalence for states based on the most recent prevalence range and average identified by the ADDM Network by 2012. IACC Budget Recommendations: $200,000 over 2 years.
8. New objective
Create mechanisms to specifically support the contribution of data from 90 percent of newly initiated projects to the National Database for Autism Research (NDAR) and link NDAR with other existing data resources by 2012. IACC Recommended Budget: $6,800,000 over 2 years.
9. New objective
Supplement existing ADDM Network sites to use population-based surveillance data to conduct at least 5 hypothesis-driven analyses evaluating factors that may contribute to changes in ASD prevalence by 2012. IACC Recommended Budget: $660,000 over 2 years.
10. New objective
Develop the personnel and technical infrastructure to assist states, territories, and other countries who request assistance describing and investigating potential changes in the prevalence of ASD and other developmental disabilities by 2013. IACC Recommended Budget: $1,650,000 over 3 years.
11. New objective
Encourage programs and funding mechanisms that expand the research workforce, enhance interdisciplinary research training, and recruit early career scientists into the ASD field by 2013. IACC Recommended Budget: $5,000,000 over 3 years.
12. New objective
Expand the number of ADDM sites in order to conduct ASD surveillance in younger and older age groups; conduct complementary direct screening to inform completeness of ongoing surveillance; and expand efforts to include autism subtypes by 2015. IACC Recommended Budget: $16,200,000 over 5 years.
13. New objective
Support 10 “Promising Practices” papers that describe innovative and successful services and supports being implemented in communities that benefit the full spectrum of people with ASD, which can be replicated in other communities by 2015. IACC Recommended Budget: $75,000 over 5 years.

OK, we might as well get this over with–here are the times the Plan mentions the “V” word:

Numerous epidemiological studies have found no relationship between ASD and vaccines containing the mercury based preservative, thimerosal (Immunization Safety Review Committee, 2004). These data, as well as subsequent research, indicate that the link between autism and vaccines is unsupported by the epidemiological research literature. However, the IOM report acknowledged that the existing population-based studies were limited in their ability to detect small susceptible subpopulations that could be more genetically vulnerable to environmental exposures.

and

Of note, the Committee receives many public comments that reflect concerns about vaccines as a potential environmental factor in autism. Some members of the public are convinced that the current data are sufficient to demonstrate that vaccines do not play a causal role in autism and argue against using limited autism research funds to do additional vaccine studies when many other scientific avenues remain to be explored. At the same time, those who believe that prior studies of the possible role of vaccines in ASD have been insufficient argue that investigation of a possible vaccine/ASD link should be a high priority for research (e.g., a large-scale study comparing vaccinated and unvaccinated groups). A third view urges shifting focus away from vaccines and onto much-needed attention toward the development of effective treatments, services and supports for those with ASD.

and

To address public concerns regarding a possible vaccine/ASD link, it will be important for the IACC to continue to coordinate with the National Vaccine Advisory Committee (NVAC), a Federal advisory committee chartered to advise and make recommendations regarding the National Vaccine Program.

under research opportunities:

Monitor the scientific literature regarding possible associations of vaccines and other environmental factors (e.g., ultrasound, pesticides, pollutants) with ASD to identify emerging opportunities for research and indicated studies.

There closest thing to an actual proposed project (i.e. something with an estimated budget) is this one:

# New objective
Support at least two studies to determine if there are subpopulations that are more susceptible to environmental exposures (e.g., immune challenges related to infections, vaccinations, or underlying autoimmune problems) by 2012. IACC Recommended Budget: $8,000,000 over 2 years.)

With the facts against them Dr. Wakefield’s supporters appeal to emotion

3 Feb

I should stop being shocked and amazed at how little groups like the Age of Autism blog think of their readership. Sorry to put it so bluntly, but it is pretty clear that they expect us all to just read what they have to say and never go to the original sources and think for ourselves.

Case in point, the GMC hearing on Dr. Andrew Wakefield. Dr. Wakefield was guilty of ethical violations in the treatment of his disabled patients. Not once, not twice but many many times. But you wouldn’t know that to read some of the reports on the blogs and even a couple in newspapers.

We have the NAA SafeMinds and TACA telling us all about how bad this ruling is. We have been told that there was “false testimony”.

OK, take a look at the actual charges. Just for a moment. Here are a few examples

1) Dr. Wakefield took money from the Legal Aid Board (LAB) for procedures paid by the NHS. He then diverted some of the LAB money to other projects.

2) Dr. Wakefield got ethical permission to do his study in December 1996, only on patients enrolled after that date. However, he had already started research on children. Here are two examples:

Child 2 had an MRI, colonoscopy and lumbar puncture in September of 1996.

Child 1 was also a research subject without ethical approval. Tests were performed which were not in the clinical interests of the child.

3) For people who promote the myth that “the only thing he did was start early”, note that Dr. Wakefield’s team did invasive tests that were not called for. For example:

Child 3 was also a research subject without ethical approval, having started before the approval. He underwent a lumbar puncture even though: “The Panel has taken into account the fact that there is no evidence in Child 3’s clinical notes to indicate that a lumbar puncture was required.”

Was this the result of some “false testimony? According to the GMC ruling, experts on both sides stated that the lumbar puncture was not clinically indicated.

Experts on both sides, Professor Rutter and Dr Thomas both considered that such a test was not clinically indicated.

Dr. Thomas is not accused by the defenders of Wakefield as “giving false testimony”.

The above are only a few of the examples of clear misconduct on the part of Dr. Wakefield.

How many times must a man be found guilty of not doing what was in his patients’ clinical interests before we are allowed to consider him as, well, someone who doesn’t always put his patient’s clinical interests first?

Kim Stagliano has taken to the Huffington Post with “The Censorship of Autism Treatment“. No mention of the actual charges. No mention of the fact that Andrew Wakefield was guilty. No mention of the fact that Andrew Wakefield’s research efforts for the past 12 years have centered on repairing his own damaged reputation, not on autism treatment.

Can you find a single mention of the word “ethics” in her post? How about any comment about the actual charges levied against Dr. Wakefield?

You know you are in trouble just with the title from this story: MMR doc’s just guilty of caring . At least that article makes one clear statement:

It [the GMC ruling] focused on the methods of research used, some of which were undoubtedly questionable, but which were performed in the name of finding solace for desperate parents convinced their children had changed for ever following their one-size-fits-all MMR injection.

Yes, you can be unethical if you are “finding solace for desperate parents”.

A blog post by the National Autism Association stated:

“Many parents of children with autism view the GMC investigation as little more than character assassination of a physician brave enough to investigate controversial issues”

Well, not this parent. Anyone who paints the GMC investigation as “character assassination” didn’t read the ruling. Seriously, trying to dismiss this fact-filled ruling as “character assassination” is just plain bizarre.

another post comments, discussing the work Dr. Wakefield’s team performed on his study subjects:

the procedures involved were routine

and

No children were harmed and no parent or guardian has complained about the care these three men provided.

Lumbar punctures are hardly “routine”. Further, there is no reason to do them if not clinically indicated. Colonoscopies are not routine, especially in patients whose symptoms don’t warrant them. Say, as in Child 1.

One child suffered a perforated bowel (in 12 places!). His family won a lawsuit against the Royal Free hospital.

High Court papers alleged that the colonoscopy procedure performed on Jack in 1998 was ‘not clinically indicated or justified’. They also claimed the ‘principal reason’ for the surgery was to further research into links between autism and bowel conditions rather than Jack’s clinical needs.

How does that not count as not “harmed”? Is it because he wasn’t one of the original 12 from the study in The Lancet?

The behavior of the Wakefield supporters is totally predictable. They have no science. They have no first (or second) tier researchers. They rely heavily on Dr. Wakefield. Who else has the perceived stature of Dr. Wakefield for them? When Brian Deer broke the story that Dr. Wakefield may have “fixed” data in his study last year, there was an immediate reaction from the Wakefield supporters: give him faux awards! Make him the keynote speaker at their conventions!

For the past year the message has been “Dr. Wakefield has not been discredited”. They’ve lost that now.

We’ve been warned that they are bringing out their big guns. Yes, David Kirby will blog about this on the Huffington Post. With apologies to Mr. Kirby, but when he’s their “ace in the hole”, you know they don’t have much.

As I finished this, David Kirby came up with his post: “The Lancet Retraction Changes Nothing”. Joining in the style of the times, Mr. Kirby also ignores the actual GMC ruling. Nothing that actually defends Dr. Wakefield against the real charges.

Seriously, go read for yourself. It’s David Kirby with his usual talking points and straw men.

I hope David Kirby is wrong. I hope that things have changed. I hope that the future is a world where the loudest voices in the autism communities fight for a better life for autistics, rather than for a political goal of recognition for bad science, badly done.

I hope.

Stanford/Packard autism researchers seek twins for brain-imaging study

2 Feb

The subject of twins and autism concordance comes up on LeftBrainRightBrain periodically. I find the questions raised to be very interesting and I’ve said a number of times I hope people take a closer look at twins.

Enter Dr. Antonio Hardan of the Lucile Packard Children’s Hospital (LPCH) at Stanford University in California. Dr. Hardan is a Child Psychiatrist with much experience in exploring brain structure in autistics. Yesterday there was a press release (which I can’t find now) calling for subjects for a twin study. The announcement is on the LPCH website.

Stanford/Packard autism researchers seek twins for brain-imaging study

Autism researchers at the Stanford University School of Medicine are recruiting twins for an investigation of the role of genetics in shaping the autistic brain.

“We’re doing a twin study to try to sort the impact of genetics on brain abnormalities in autism from the impact of the environment,” said lead scientist Antonio Hardan, MD, who is a child psychiatrist at Lucile Packard Children’s Hospital and associate professor of psychiatry and behavioral sciences at Stanford. Hardan’s team will use magnetic resonance imaging to scan the brains of 120 pairs of twins, some with autism and some without, to look for gene-brain associations.

Previous research has indicated about 75 to 80 percent of autism is explained by genetics, Hardan said. This means that if one member of a pair of identical twins has autism, the other will usually be affected. Having a fraternal (non-identical) twin or other sibling with autism raises a child’s likelihood of an autism diagnosis, but not as much.

Still, no one knows the degree to which genetic factors explain distinct structural and chemical characteristics in the brains of autistic individuals, which may include differences in total brain size and in the corpus callosum and amygdala.

Hardan’s research team will compare the level of similarity in brain structures of identical twins, who share all their genes, with the brain similarities of fraternal twins, who share half of their genes. They will also compare pairs of twins with autism with typically developing (non-autistic) twins to gain insight into which developmental patterns are distinct to autism. They then hope to figure out whether and to what degree there is a correlation between genetic profiles and the brain metabolites and structures of people with autism.

The team is seeking same-sex twin pairs aged 3 to 14. Study subjects can be identical or non-identical twins. The scientists plan to scan 80 pairs in which one or both twins have autism, and 40 typically developing pairs in which neither twin has autism. The scanning method, MRI, is non-invasive and does not involve any radiation exposure. All subjects will also receive standard cognitive and IQ assessments, as well as a battery of diagnostic tests for autism.

Testing will take four to five hours over two consecutive days, and each twin who completes the testing will be compensated $100. Subjects will receive summaries of their cognitive testing results, and confirmation of whether they are identical or fraternal twins. The twins’ families will also be compensated for travel expenses to and from Stanford.

“The scientific value of the study is a major one,” Hardan concluded. “We don’t know how much is inherited in terms of specific brain abnormalities in autism, and we also need to learn more about how environmental factors play into the development of the autistic brain. This study will help us gain that understanding.”

Hardan’s collaborators on the study include Joachim Hallmayer, MD, associate professor of psychiatry and behavioral sciences, and Allan Reiss, MD, professor of psychiatry and behavioral sciences and of radiology. Reiss also directs the Center for Interdisciplinary Brain Sciences Research at Stanford and practices as a child psychiatrist at Packard Children’s.

To obtain more information or volunteer for the trial, contact the study coordinator, Sue Cleveland, at (650) 723-7809 or cleve@stanford.edu.

There is some interesting research already on twins. One study (I only have the abstract so far) just came out last year: Gyrification patterns in monozygotic twin pairs varying in discordance for autism.

Kates WR, Ikuta I, Burnette CP.

Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse, New York 13210, USA. katesw@upstate.edu

In order to disentangle genetic and environmental contributions to cortical anomalies in children with autism, we investigated cortical folding patterns in a cohort of 14 monozygotic (MZ) twin pairs who displayed a range of phenotypic discordance for autism, and 14 typically developing community controls. Cortical folding was assessed with the gyrification index, which was calculated on high resolution anatomic MR images. We found that the cortical folding patterns across most lobar regions of the cerebral cortex was highly discordant within MZ twin pairs. In addition, children with autism and their co-twins exhibited increased cortical folding in the right parietal lobe, relative to age- and gender-matched typical developing children. Increased folding in the right parietal lobe was associated with more symptoms of autism for co-twins. Finally, the robust association between cortical folding and IQ observed in typical children was not observed in either children with autism or their co-twins. These findings, which contribute to our understanding of the limits of genetic liability in autism, suggest that anomalies in the structural integrity of the cortex in this PDD may disrupt the association between cortical folding and intelligence that has been reported in typical individuals, and may account, in part, for the deficits in visual spatial attention and in social cognition that have been reported in children with autism.

I find this to be rather interesting. “We found that the cortical folding patterns across most lobar regions of the cerebral cortex was highly discordant within MZ twin pairs.” In other words, the physical brain structure is different within “identical” twin pairs. Recall the twin pairs in this study “displayed a range of phenotypic discordance for autism”. It is hard for me to simplify that without oversimplification, but the twins do not have the same autistic traits, and perhaps differing ASD diagnoses.

There is also an earlier study by Dr. Hardan and colleagues that seems relevant, even though it is not a twin study: Increased frontal cortical folding in autism: a preliminary MRI study.

Hardan AY, Jou RJ, Keshavan MS, Varma R, Minshew NJ.

Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. hardanay@upmc.edu

The gyrification index (GI), the ratio of total to outer cortical contour, was applied to measure the cerebral folding patterns in autism. GI was examined on a frontal coronal slice obtained from MRI scans of 30 nonmentally retarded individuals with autism and 32 matched healthy controls. In the autistic group, left frontal GI was higher in children and adolescents but not in adults. Cortical folding was decreased bilaterally with age in the total autistic sample but not in controls. These preliminary findings suggest that the gyrification patterns in autism may be abnormal, which could be related to the various cortical anomalies observed in this disorder.

Below is an image from the Hardan study. The “gyrification ratio” is a measure of the inner contour to the outer contour.

Diagram showing manual traces of cortical contours

Manually traced inner and outer cortical contours used for measuring the gyrification index.

The results of the Hardan study were “preliminary”, and there was a statistically significant difference observed in those measurements. What was observed was “Interestingly, there was a significant decrease in the frontal gyrification patterns with age in the autistic group (right side: r=?0.44, P=0.012; left side: r=?0.48, P=0.006), which was not seen in controls (right side: r=?0.12, P=0.51; left side: r=?0.065, P=0.72). ”

I find this interesting–the GI (consider it the “folding” in the brain) differs by age for the autistics but not for the controls.

Again, I find the proposed twin study to be interesting and potentially very valuable. I hope Dr. Hardan can find enough study subjects to complete the study. There probably are not a lot of parents of autistic twins who live near Stanford reading this blog, but who knows?

Lancet retracts Wakefield paper

2 Feb

Following the judgment of the UK General Medical Council’s Fitness to Practise Panel on Jan 28, 2010, it has become clear that several elements of the 1998 paper by Wakefield et al1 are incorrect, contrary to the findings of an earlier investigation.2 In particular, the claims in the original paper that children were “consecutively referred” and that investigations were “approved” by the local ethics committee have been proven to be false. Therefore we fully retract this paper from the published record.

Source.

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