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Scientific fraud in the UK: The time has come for regulation

3 Aug

In a recent article in the Guardian, Brian Deer poses the question of whether regulation needs to be applied to scientific research. The article, Scientific fraud in the UK: The time has come for regulation, Mr. Deer states:

Fellows of the Royal Society aren’t supposed to shriek. But that’s what one did at a public meeting recently when I leapt onto my hobbyhorse: fraud in science. The establishment don’t want to know. An FRS in the audience – a professor of structural biology – practically vaulted across the room in full cry. What got this guy’s goat was my suggestion that scientists are no more trustworthy than restaurant managers or athletes.

Restaurant kitchens are checked because some of them are dirty. Athletes are drug-tested because some of them cheat. Old people’s homes, hospitals and centres for the disabled are subjected to random inspections. But oh-so-lofty scientists plough on unperturbed by the darker suspicions of our time.

Mr. Deer’s article mentions a just release UK Government report “Peer review in scientific publications” Here is the final paragraph from the summary for that report:

Finally, we found that the integrity of the peer-review process can only ever be as robust as the integrity of the people involved. Ethical and scientific misconduct—such as in the Wakefield case—damages peer review and science as a whole. Although it is not the role of peer review to police research integrity and identify fraud or misconduct, it does, on occasion, identify suspicious cases. While there is guidance in place for journal editors when ethical misconduct is suspected, we found the general oversight of research integrity in the UK to be unsatisfactory. We note that the UK Research Integrity Futures Working Group report recently made sensible recommendations about the way forward for research integrity in the UK, which have not been adopted. We recommend that the Government revisit the recommendation that the UK should have an oversight body for research integrity that provides “advice and support to research employers and assurance to research funders”, across all disciplines. Furthermore, while employers must take responsibility for the integrity of their employees’ research, we recommend that there be an external regulator overseeing research integrity. We also recommend that all UK research institutions have a specific member of staff leading on research integrity.

I find it odd that they are focusing on peer-review, which seems to me to be a narrow field of research integrity. That said, the report is recommending that “an oversight body for research integrity” be formed.

Back to Mr. Deer’s article. He quotes a Dr. David Taylor on why such oversight might not be needed:

“It is important to recognise that in the long term it matters little if published material is inaccurate, incompetent or even fraudulent, since the advance of the scientific canon only uses that material which turns out to fit the gradually emerging jigsaw,” is how Dr David Taylor, a former executive at AstraZeneca, expressed this tenet in a recent submission to the House of Commons science and technology committee, which publishes a report today.

I think that Dr. Taylor is taking a rather idealistic view of research. Yes, there is a self-correcting nature to research. Those results which are wrong will not be replicated and will, over time, fade.

But, how much time does it take for the self-correction? Autism research provides, unfortunately, a great example of the persistence of poor level, even fraudulent, research. For example, the concept of an epidemic caused by vaccines, either through the MMR vaccine or through thimerosal, was promoted by research which ran the gamut from reasonable speculation to outright fraud. One of the prime examples of research fraud which the committee cited in the report is on the MMR/autism hypothesis.

The problem is that while we wait for this “self correction”, real people suffer the consequences. Aside from the mental anguish it has caused, the vaccine/autism epidemic idea has spawned an industry of alternative medicine practitioners and treatments. These treatments run the gamut from worthless/harmless to powerful medicine and potentially dangerous.

Researchers, especially those who are publicly funded and/or publish, hold a public trust. Certainly, researchers hold a trust to use public funds wisely. Unfortunately, published research, even bad published research, is used to promote non-science agendas. The term “tobacco science” gets thrown around a lot, but the fact is that sometimes journal publications are less about reporting results as making a political or business statement. This happens for both “big pharma” and for “little pharma“. The harm from research fraud, or even just heavily biased research, is not limited to medicine. But I would posit that the most harm is done in the area of medical research.

As an American, I will be only an observer in if/how the UK pursues regulation of research integrity. However, the damage from research fraud knows no boundaries. I don’t know if there is an optimal solution which reduces the damage of research fraud through regulation while still promoting the freedom of self-direction for researcher. Is there a need? I’d say yes. Taking the Wakefield affair as an example, there may be few examples of really damaging fraudulent research, but the damage of even these few examples can be very great.

Congress delays hearing on autism bill

2 Aug

The Santa Monica Dispatch is reporting that committee hearings on the Combating Autism Reauthorization Act have been pushed off to September:

e U.S. Senate Health, Education, Labor and Pensions (HELP) Committee has just announced that it is postponing a meeting on the Combating Autism Reauthorization Act (CARA) until September 7. The meeting had been scheduled for this Wednesday August 3, but Congress is apparently so exhausted by its represensible behavior during the debt ceiling debate that it’s giving itself a five-week recess. With pay.

http://www.santamonicadispatch.com/2011/08/congress-delays-hearing-in-autism-bill/

The Combating Autism Act reinstated the Interagency Autism Coordinating Committee (IACC) which creates a strategic plan for autism research in the US. More importantly, the CAA authorizes congress to appropriate money for autism specific research.

The CAA is set to end (sunset) on September 30. This leaves very little time from committee hearing to any potential vote by the legislature.

Lack of association between autism and four heavy metal regulatory genes

30 Jul

One question that has been discussed for some time is the hypothesized role of mercury as a potential cause of autism. The basic idea is that administrative prevalences of autism went up coincident with increases in mercury exposure from vaccines. Plus, it was asserted that autism symptoms are similar to the symptoms of mercury poisoning (they aren’t).

Part of the mercury model held that there could be a genetic susceptibility to mercury in a subset of children.

Researchers at Vanderbilt University have explored the question by testing autistics for genes involved in how the body processes mercury. They did not find any link between the four genes they screened and autism.

Of course one could argue that some other gene or genes are important. One would then need to explain why mercury exposure from vaccines does not increase the risk of autism.

The paper:
Lack of association between autism and four heavy metal regulatory genes.

Here’s the abstract.

Neurotoxicology. 2011 Jul 20. [Epub ahead of print]
Lack of association between autism and four heavy metal regulatory genes.
Owens SE, Summar ML, Ryckman KK, Haines JL, Reiss S, Summar SR, Aschner M.
Source
Department of Pediatric Toxicology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Abstract
Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to “safe” Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg’s metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher’s exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.

Percutaneous endoscopic gastrostomy and gastro-oesophageal reflux in neurologically impaired children

29 Jul

A large amount of what goes into a doctor’s decision making process is based on the communication between doctor and patient. How can you tell if someone has heartburn if you don’t understand the ways that person is communicating? Or, to put it more generally, how does the medical system appropriately serve those with difficulty communicating or with sensory issues?

This recent paper, Percutaneous endoscopic gastrostomy and gastro-oesophageal reflux in neurologically impaired children (full paper online), while not specific to autism, shows that with a lot of extra work, one can get valuable diagnostic information.

Here is the abstract:

Abstract

AIM:To investigate the effects of percutaneous endoscopic gastrostomy (PEG) feeding on gastro-oesophageal reflux (GOR) in a group of these children using combined intraluminal pH and multiple intraluminal impedance (pH/MII).

METHODS: Ten neurologically impaired children underwent 12 h combined pH/MII procedures at least 1 d before and at least 12 d after PEG placement.

METHODS: Prior to PEG placement (pre-PEG) a total of 183 GOR episodes were detected, 156 (85.2%) were non-acidic. After PEG placement (post-PEG) a total of 355 episodes were detected, 182 (51.3%) were non-acidic. The total number of distal acid reflux events statistically significantly increased post-PEG placement (pre-PEG total 27, post-PEG total 173, P = 0.028) and the mean distal pH decreased by 1.1 units. The distal reflux index therefore also significantly increased post-PEG [pre-PEG 0.25 (0-2), post-PEG 2.95 (0-40)]. Average proximal pH was lower post-PEG but the within subject difference was not statistically significant (P = 0.058). Median number of non-acid GOR, average reflux height, total acid clearance time and total bolus clearance time were all lower pre-PEG, but not statistically significant.

CONCLUSION: PEG placement increases GOR episodes in neurologically impaired children.

It is a small study. They place feeding tubes in the children and measure acid events (GOR). The feeding tubes increase the number of acid events.

Gastrointestinal disease has been a major topic within the autism communities for some time. While most of the discussion tends to focus upon whether this is highly prevalent and whether this is somehow linked to autism causation, much less time has been focused upon the actual diagnosis and treatment. Doctors will need extra time and effort in order to make the diagnoses and treat individuals where communication is limited.

Mark Geier: under scrutiny in more states

29 Jul

In Home Autism doctor here under scrutiny, The St. Louis Post Dispatch discusses investigations ongoing in Illinois:

A autism doctor who operates clinics in St. Peters and Springfield, Ill., has been suspended in two states for alleged mistreatment of children.

Dr. Mark Geier has been accused of misdiagnosing children with early puberty and treating them with high doses of Lupron, a drug used to suppress the hormone testosterone.

A hearing will be held on August 22nd to consider Dr. Geier’s license in the state of Illinois.

The Post Dispatch notes that Dr. Geier’s hypotheses and methods are far from generally accepted:

Dr. John Constantino, a psychiatry professor and leading autism researcher at Washington University, said Geier “understands the tools of science but has applied them in questionable ways” to justify specific treatments.

“There is currently no scientific evidence to support the clinical use of Lupron to treat autism in anything other than carefully conducted research trials,” Constantino said.

Autism News Beat in Castration doctor’s license now suspended in four states notes:

Dr. Mark Geier, the Maryland physician who chemically castrates disabled children, is still licensed to practice medicine in seven states, down from eleven. Four states have suspended or revoked his privileges since April 27, when his home state took action against him. Washington followed on May 26, then Virginia on June 9. On June 29, Indiana issued an emergency 90-day suspension, citing the Maryland action.

Onset patterns in autism: correspondence between home video and parent report

27 Jul

Regression is a major topic in autism. Children who lose abilities at a very young age. In Onset patterns in autism: correspondence between home video and parent report, Sally Ozonoff, Ph.D. and a team of researchers at the U.C. Davis MIND Institute looked at the developmental trajectories of children, autistic and non autistic. They reviewed home videos of the children to map those trajectories. They monitored social communication as a function of time.

What they found was even more complex than expected. Instead of finding that some children show low levels of social communication from very early in life. A second group has early high levels of social communication, followed by significant decreases over time (regression). But, there was a third group: a group which was more typical in development followed by not regression, but a plateau in progress in social communication.

The numbers of children in the study are small (53 autistic children), making it unlikely to get a precise idea of what fraction of the children follow each trajectory. According to the IMFAR abstract for this study:

Bayesian Information Criteria were used to select the number of trajectories that best fit the data. There was strong support from coded home video for 3 onset trajectories. The first “early onset” trajectory (n = 20) displayed low rates of social-communication behavior at all ages. The second “regression” trajectory (n = 20) displayed high levels of social-communication behavior early in life and significantly declined over time. The third “plateau” trajectory (n = 12) was similar to the typical children early in life but did not progress as expected. There was no support for a mixed (early signs + regression) trajectory.

Here is the abstract for the published paper:

OBJECTIVE:
The onset of autism is usually conceptualized as occurring in one of two patterns, early onset or regressive. This study examined the number and shape of trajectories of symptom onset evident in coded home movies of children with autism and examined their correspondence with parent report of onset.

METHOD:
Four social-communicative behaviors were coded from the home video of children with autism (n = 52) or typical development (n = 23). All home videos from 6 through 24 months of age were coded (3199 segments). Latent class modeling was used to characterize trajectories and determine the optimal number needed to describe the coded home video. These trajectories were then compared with parent reports of onset patterns, as defined by the Autism Diagnostic Interview-Revised.

RESULTS:
A three-trajectory model best fit the data from the participants with autism. One trajectory displayed low levels of social-communication across time. A second trajectory displayed high levels of social-communication early in life, followed by a significant decrease over time. A third trajectory displayed initial levels of behavior that were similar to the typically developing group but little progress in social-communication with age. There was poor correspondence between home video-based trajectories and parent report of onset.

CONCLUSIONS:
More than two onset categories may be needed to describe the ways in which symptoms emerge in children with autism. There is low agreement between parent report and home video, suggesting that methods for improving parent report of early development must be developed.

The last statement in the results is obviously intriguing. “There was poor correspondence between home video-based trajectories and parent report of onset.”

Here is the segment of the IMFAR abstract:

There was poor correspondence between parent report and home video classifications (kappa = .11, p = .30). Only 9 of 20 participants whose home video displayed clear evidence of a major decline in social-communication behavior were reported to have had a regression by parents. Only 8 of 20 participants with evidence of early delays in social-communication on video were reported to demonstrate an early onset pattern by parents. Of the 10 whose parents described a plateau, only 3 had home video consistent with this pattern.

So, none of the three groups were able to correctly recall the trajectory. Not the parents of kids who regressed. Not the parents of kids who plateaued. Not the parents of kids who had early onset autism.

As parents we’d like to see ourselves as the experts of our children. And, frankly, we are. No one else knows them like we do. But that doesn’t make us infallible.

The study was presented at IMFAR and Shannon Rosa wrote about it for The Thinking Person’s Guide to Autism.

Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism

18 Jul

The results of the long-awaited California Autism Twin Study (CATS) have been published. The article, Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism appears in the Archives of General Psychiatry and is open-access (i.e. free). The study set out “To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.”

The basic idea of a twin study is fairly straighforward: “identical” (or monozygotic, MZ) twins share 100% of their DNA, “fraternal” (dizygotic, or DZ) twins share about 50% of their DNA. If a condition is purely genetic, identical twins will both have the condition or not have the condition. The percentage of twins with a condition is called concordance. High concordance implies a highly genetic condition.

Early twin studies showed a high concordance. These studies were relatively small. The first study, Infantile autism: a genetic study of 21 twin pairs, was published in 1977 and included, as you might guess, only 21 twin pairs. Of these, 10 DZ and 11 MZ twins. There were three twin studies which made up the main body of knowledge suggesting a strong heritability of autism, including a total of 56 pairs.

The California Twin study sought to take a much closer look. First by including a much greater number of twin pairs, and second by including modern diagnostic methods. They used the California Department of Developmental Services as a resource to identify twin pairs with at least one autistic. The CDDS database has advantages and disadvantages. First, the database is large and covers fairly diverse state. This is important when you consider that (a) only about 1% of the population is autistic and (2) only about 3.2% of the population are twins. That means about 1 in 3000 are twins+autistic.

The disadvantages of the CDDS as a resource include the fact that not everyone with an ASD qualifies for services or is correctly classified. Of those who qualify, inclusion in the CDDS is voluntary. Technically, the CDDS serves only those with autistic disorder or those in the “fifth category” which includes “…disabling conditions found to be closely related to mental retardation or requiring treatment similar to that required for individuals with mental retardation.” This would limit the ability to identify ASD concordance. For example, twins who both have Asperger syndrome.

One major strength of the study was the use of clinical assessments plus parent interviews for diagnosis. They did not rely upon the CDDS reports for diagnoses. Also, the study determined twin status (MZ or DZ) through genetic testing, something which wasn’t available when the first twin studies were performed.

Here is the abstract for the study:

Context Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins.

Objective To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment.

Design, Setting, and Participants Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services.

Main Outcome Measures Structured diagnostic assessments (Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD).

Results For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD).

Conclusion Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

The concordance values are 77% for male MZ twins and 50% for female MZ twins. These values are high. But the heritability estimates are influenced not just by the MZ twin concordance, but by the difference between MZ and DZ concordance. Consider if 100% of “identical” twins had a condition. This doesn’t necessarily mean that the condition is fully caused by hertiablity if, say, 100% of the “fraternal” twins also had the condition. In the California Twin study, DZ concordance values were relatively high (31% for males and 36% for females).

Based on these values, the authors calculate that shared environment accounts for 55% of the risk of autism and 37% for genetic heritability. There are big “error bars” (or confidence intervals) for the concordance and heritablity values. It is worth noting that the concordance values here are similar to those reported recently by Bearman’s team at Columbia (40-50% pairwise concordance for MZ twins. This study also used the CDDS as a resource, but did not use clinical assessments) and Goldsmith’s group at the University of Wisconsin (43% pairwise concordance). These studies also concluded that genetic heritability was lower than previously thought.

The authors concluded their paper:

Our study provides evidence that the rate of concordance in dizygotic twins may have been seriously underestimated in previous studies and the influence of genetic factors on the susceptibility to develop autism, overestimated. Because of the reported high heritability of autism, a major focus of research in autism has been on finding the underlying genetic causes, with less emphasis on potential environmental triggers or causes. The finding of significant influence of the shared environment, experiences that are common to both twin individuals, may be important for future research paradigms. Increasingly, evidence is accumulating that overt symptoms of autism emerge around the end of the first year of life. Because the prenatal environment and early postnatal environment are shared between twin individuals, we hypothesize that at least some of the environmental factors impacting susceptibility to autism exert their effect during this critical period of life. Nongenetic risk factors that may index environmental influences include parental age, low birth weight, multiple births, and maternal infections during pregnancy. Future studies that seek to elucidate such factors and their role in enhancing or suppressing genetic susceptibility are likely to enhance our understanding of autism.

The authors can be heard on KQED in San Francisco discussing the paper.

http://www.kqed.org/assets/flash/kqedplayer.swf

In a companion commentary on Archives of General Psychiatry, Is Autism, at Least in Part, a Disorder of Fetal Programming?, Peter Szatmari comments on the shift in perception based on the new heritability estimates: “The autism field can now join the chorus and ask, “Where did all the heritability go?” We now appear to have an answer, at least in part: those original estimates were inflated.”

“Inflated” seems a bit of a loaded word. There are big error bars on the current study, there were even bigger ones in the old studies. What I found very interesting was this peak at an upcoming paper by the Baby Siblings Research Consortium:

The high DZ concordance rate is consistent with estimates reported from the Baby Siblings Research Consortium. In these studies, infant siblings of children with ASD are followed up from birth to age 36 months so that risk can be calculated in a prospective fashion. The latest report from the Baby Siblings Research Consortium suggests that the risk is upwards of 20%, which is slightly less than the DZ rate provided by Hallmayer and colleagues (31%-36% for ASD). The confidence intervals of the estimates overlap to be sure, but this may also suggest potential ascertainment bias for concordant as opposed to nonconcordant DZ twin pairs or that twinning itself is a risk factor for ASD.

(reference: Ozonoff S, Young G, Carter AS, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson SE, Carver L, Constantino J, Dobkins K, Hutman T, Iverson J, Landa R, Rogers S, Sigman M, Stone W. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium Study. Pediatrics. In press.)

They commentary poses some good questions about potential bias in the California Autism Twin Study:

One must ask whether there was any bias artificially reducing concordance in the study by Hallmayer and colleagues. One possibility is missing data, which are substantial. Another possibility is differential misclassification. It is not inconceivable that parents are more likely to rate MZ twins with a disability as more dissimilar than DZ twins. There may be an unconscious effort on their part to see one twin as less affected than the other. Such reporting effects, known as sibling deidentification, have been reported for twin studies of temperament.8 It would be extremely interesting to see whether concordance rates differ by instrument, ie, the Autism Diagnostic Interview–Revised, which is based on parental report, vs the Autism Diagnostic Observation Schedule, which is based on an independent observer. If the sensitivity of the measurement tool is less in MZ twins than in DZ twins, a smaller difference in observed concordance rates would be expected compared with true concordance rates based on no measurement error.

and:

A third threat to the validity of the findings is that twinning itself might be a risk factor for ASD, so that the heritability estimates generated would not be generalizable to the population of nontwin children with ASD. There may be some factor associated with twinning such as maternal age, coming from a monochoreonic placenta, prematurity, or in vitro fertilization that could place twins at risk for ASD. There is in fact some evidence that twins have a higher rate of autism than nontwins,9 but further work needs to be undertaken to provide better evidence.

It’s taken 34 years since the first autism twin study until the much larger California Autism Twin Study. This has been a time consuming and expensive undertaking. I doubt there will be a chance in the near future for a larger study to address the issues laid out above. This doesn’t preclude some other studies to clarify some questions, but the California Autism Twin Study will likely stand for some time before being challenged or confirmed.

What’s up with Fox News and promoting bad autism science and medicine

15 Jul

OK, it’s anecdotal. But from my perspective of all the networks, Fox just seems to be the most open to bad science and medicine reporting. CBS has Sharyl Attkisson, and her work has been far from excellent over the years. But Fox just seems to be the “go-to” news outlet for those pushing vaccine causation and unproven medical treatments.

Case in point, Fox 9 in the Twin Cities. A recent story: Investigators: Hyperbaric Autism Care.

http://www.myfoxtwincities.com/video/videoplayer.swf?dppversion=10588

Investigators: Hyperbaric Autism Care: MyFoxTWINCITIES.com

There just isn’t any evidence that HBOT works for autism. There isn’t even a good theory for why it would work. Listen to the story, they basically have it right: the brain will absorb more oxygen. In turn this will help treat autism.

That’s about it for the theory: oxygen should be good. More should be better. I.e. hyperbarics will treat autism. When it goes by fast, it sounds like they have some idea what they are talking about. But there isn’t anything there.

Generation Rescue: taking another small step away from the brink?

14 Jul

Generation Rescue has over the years been one of the more vocal promoters of the vaccines-cause-autism notion. Like any organization, they have changed over the years and their website reflects that. Their website started out with the title “Autism Mercury Chelation” and a very simple (and wrong) statement:

Generation Rescue believes that childhood neurological disorders such as autism, Asperger’s, ADHD/ADD, speech delay, sensory integration disorder, and many other developmental delays are all misdiagnoses for mercury poisoning.

Of course, later during the early years of Jenny McCarthy, when Generation Rescue became “Jenny McCarthy’s autism organization. By this point, GR had a prominent link on the main page to “vaccines”. This included a page with Generation Rescue recommended vaccine schedules. Their “favorite” being a schedule that offered no protection against many diseases, including measles, mumps, rubella, pertussis, diptheria and tetanus.

They had a page of “science”, including statements claiming that Andrew Wakefield’s 1998 paper linked MMR to autism (a position Mr. Wakefield has tried to distance himself from in the past few years):

“This study demonstrates that the MMR vaccine triggered autistic behaviors and inflammatory bowel disease in autistic children.”

They had a science advisory board, which included S. Jill James, Ph.D., Richard Deth, Ph.D., Woody R. McGinnis, M.D. and Jerry Kartzinel, M.D.. Not exactly heavy hitters, but at least a couple of people who actually publish in journals.

Times have changed again. The website is revamped. And vaccines seem to be much less prominent. For example, in the current version of the Generation Rescue website, I can’t find “recommended” vaccine schedules (they refer people to Dr. Bob Sears). A search for Wakefield shows he is only mentioned once “Studies by researchers: Horvath, Wakefield, Levy, and Kushak highlight a myriad of gut problems present in children with autism, including abnormal stool (diarrhea, constipation), intestinal inflammation, and reduced enzyme function”. The science advisory board is down to one person (Jerry Kartzinel) and an unnamed “cohesive group of professionals committed to healing and preventing autism”.

Sure, it’s still not a place I would recommend to anyone, especially a parent who just found out their kid is autistic. But just a few short years ago the trajectory was increasing with the vaccine discussion, not decreasing.

Autism Spring

5 Jul

Autism Spring is a recent blog post by Dr. Thomas Insel. Dr. Insel is the director of the National Institute of Mental Health (NIMH) and the chair of the Interagency Autism Coordinating Committee.

As a rule, I try to not copy other articles in their entirety. As a taxpayer, I feel that work by the government is in a different category, and so I present the entire article below.

I find it very interesting to read what Dr. Insel finds important in autism research. At the same time, I think it is important to present this without much in the way of commentary (until whatever discussion unfolds, of course).

Looking back over NIMH related events these past few months, one might wonder if this has been Autism Spring. It has certainly been a busy season for autism spectrum disorder (ASD): a White House meeting, unprecedented press coverage, and the largest International Meeting for Autism Research (IMFAR) to date. But perhaps most exciting has been the early scientific harvest evident in a series of high-profile papers published over the past two months. Some of these discoveries with autism have implications for mental disorders like schizophrenia and mood disorders, which increasingly are being addressed as neurodevelopmental disorders.

While the new findings range from epidemiology to new diagnostic tests, here I will focus on new insights into the molecular basis of autism. Three studies, written up in the June issue of Neuron, based their findings on data from the Simons Simplex Collection.1,2,3 The Simons Foundation funded the collection of careful clinical descriptions and DNA from over 1,000 children with autism who were the only affected member of their families; such families are referred to as simplex, in contrast to multiplex families, which have multiple affected members. The new reports look specifically at copy number variations (CNVs). These are rare, structural changes in the genome leading to a deletion or duplication of a segment of DNA. Many of these are de novo, meaning that the duplication or deletion is not found in the genome of either parent but develop in the DNA of germ cells (egg or sperm) over the life of one parent. Small de novo changes in DNA sequence, which occur in all of us, demonstrate that effects can be genetic without necessarily being inherited. And, of course, these germ cell changes may be the result of environmental factors, increasing with parental age.

The results are both intriguing and frustrating. Intriguing, in that children with ASD were found to have many more CNVs. These CNVs were more likely to be larger and more frequently involved specific genes than those found in unaffected siblings. But only 1 in 38 affected children had a recurrent CNV, meaning a CNV that appeared in any of the other children in the study. Of these recurrent CNVs, six genomic regions were discovered to be associated with ASD, including four duplications of the chromosome 7q11.23 region. This region is deleted in Williams-Buren syndrome, a disorder with hyper-social, hyper-verbal behavior that, in some ways, appears as the inverse of the autism phenotype. Unfortunately, the papers did not describe whether these recurrent CNVs were associated with distinct clinical characteristics.

The frustration comes from the relative rarity and complexity of these de novo CNVs. In two separate studies of this same sample using different techniques, only about 8 percent of ASD children in simplex families had CNVs. Add this number to the 8 percent with a mutation known to cause autism, such as Fragile X or tuberous sclerosis, and that still leaves more than 80 percent of ASD children with no evident genomic cause for their disorder. Traditional estimates of the heritability of ASD range as high as 90 percent. It is quite possible that these heritability estimates were too high, but even if the heritability were less, as Scharff and Zoghbi noted in an essay that accompanied these three Neuron papers, “the results are humbling.”4

Of course, there are more genomic risk factors to be found, given that the CNVs identified in these studies are large (100,000 bases or greater). As the technology for genomic research improves, smaller CNVs are likely to be identified. These papers estimate that there may be 200-300 CNVs in the genome contributing to ASD. The next step in this journey will involve sequencing all the coding regions of the genome, no doubt with even more variations emerging.

But there are more questions than answers in these projections. Many CNVs are incidental (2 percent occur in unaffected siblings), many different genes may be affected by the known CNVs, and the biological significance of any of these mutations remains to be determined. Indeed, an independent paper looking at the interaction of proteins from genes implicated in ASD found networks centered on two synaptic proteins: Shank 3 and PSD95.5 A separate analysis of the genes thought to be implicated in ASD identified a network that included genes involved in synapse formation, axon targeting, and neuronal motility.6 All of this suggests that, from a genomic perspective, autism is a synaptic disease.

Why is this important? If nothing else, these humbling results beg for more exploration of the brain. And one of the most exciting studies , just out, reports that RNA expression patterns in post-mortem brains yield some surprising clues. RNA is the key intermediary for translating DNA into protein. Patterns of RNA expression define which proteins will be expressed, determining the function of each cell. In ASD brains, the expected differences in expression between different regions of the brain are less distinct, as if mature cortical patterns have not developed. While the differences in expression are complex, they converge around a few key pathways and may reflect differences in RNA splicing. For instance, with brain maturation, genes are spliced in different regions to yield different fragments of RNA and different protein products. We need much more study of this process in ASD, but this initial project of frontal and temporal cortex suggests that whatever the DNA variations in ASD may be, the RNA fragments are strikingly abnormal.

If the CNVs discovered in genomic DNA reflect a fundamental genomic instability in ASD, could there be somatic mutations (mutations found in neurons but not in blood cells) in ASD brains? Perhaps the biology of cancer, with mutations in oncogenes and tumor suppressor genes found only in the tumor, will be a useful model for the biology of ASD, with mutations found only in the cortex.

Oliver Wendell Holmes once said, “I wouldn’t give a fig for the simplicity on this side of complexity; I’d give my right arm for the simplicity on the far side of complexity.” We are, unfortunately, not near the far side of complexity of autism. These recent studies raise questions about the limits of genetics, even with the enormous power of our current techniques. Genetic signals will be complex and may not converge as we would hope around a simple developmental mechanism or pathway. Post-mortem brain analysis may be highly informative, but we have little tissue from ASD children, and comparisons with age-matched tissue continue to be a challenge.

The great uncharted territory of environmental factors remains, which might begin to explain the infrequent mutation rate and apparent increase in autism prevalence. Here, we are stymied by a different kind of complexity. Most evidence points to environmental factors acting in the second trimester, two or more years before a diagnosis of ASD. Several studies funded by NIH are looking for differences in the gestational environment of children later diagnosed with ASD. The answers — and there will be answers — will no doubt merge genetic risk and environmental exposure to help us reach the far side of the complexity of ASD.

1) Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011 Jun 9;70(5):886-97. PubMed PMID: 21658582.
2) Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Davis Wright NR, Dhodapkar RM, Dicola M, Dilullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O’Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, State MW. Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism. Neuron. 2011 Jun 9;70(5):863-85. PubMed PMID: 21658581.
3) Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron. 2011 Jun 9;70(5):898-907. PubMed PMID: 21658583.
4) Schaaf CP, Zoghbi HY. Solving the autism puzzle a few pieces at a time. Neuron. 2011 Jun 9;70(5):806-8. PubMed PMID: 21658575.
5) Sakai Y, Shaw CA, Dawson BC, Dugas DV, Al-Mohtaseb Z, Hill DE, Zoghbi HY. Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med. 2011 Jun 8;3(86):86ra49. PubMed PMID: 21653829.
6) Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe MJ, Geschwind DH. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011 Jun 16;474: 380-86. PMID: 21614001.

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