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Autism ‘levelling off’?

3 Nov

A new paper in Pediatrics asks:

…whether the increasing prevalence of autism, on the basis of educational data, in Wisconsin between 2002 and 2008 was uniform in all school districts or was greatest in districts with lower baseline (2002) prevalence.

In other words, was there a greater increase in the school districts where the prevalence of autism had previously been lowest? In this ‘catch up’ scenario, there was _still_ no epidemic of autism just a gradual levelling out as the school districts with lower prevalence in 2002 ‘caught up’ with the school districts with the higher prevalence in 2002.

In order to answer this question, the authors

…grouped [the districts] into 8 categories (octiles) according to their baseline prevalence, and prevalence trends were plotted according to octile.

The results were as expected – whilst the _overall_ prevalence increased from 4.9 cases per thousand to 9 cases per thousand, in each different octile, the results were not uniform. If an octile already had near 9 cases per thousand then they increased by a very small amount. If an octile was closer to the 4.9 starting point then they increased over the same amount of time (2002 – 2008) by a much larger amount until both reached the same amount – roughly 1%.

As we know from other studies, a prevalence of 1% seems to be emerging from differing areas of the world as well as different areas of the US. As John Harrington states in a companion commentary, this study shows

There seem to be no “hot spots” or high-risk areas with some ominous environmental toxin that can be postulated; it is more likely that educational services for autism were better coordinated in 1 area versus another.

Autism services are playing catch up in the school system in the US according to this paper. Thats all. Still no epidemic.

Change.org ask ‘Did the Anti-Vaccination Movement Cause the Whooping Cough Epidemic?’

2 Nov

A great post over at Change.org asks the question and delivers the right answer – yes, yes they did. It also targets the right org as being responsible – Barbara Loe Fischer’s anti-vaccine group NVIC.

Whooping cough is making a comeback. This summer, the highly contagious upper respiratory infection struck more than 6,000 people in California — the most cases since 1950. Ten people died, all infants.

…

The stubborn belief that vaccines are harmful to a child’s health show just how damaging — even deadly–unscientific movements like the NVIC’s are. And how wrong.

…

…not vaccinating children erodes the “wall of immunity” that keeps all kids safe from life-threatening diseases. When infections have fewer potential hosts, there is less of a chance that those infections will be able to spread from child to child. When kids are vulnerable to nasty germs — because their parents don’t immunize them — they put their friends and classmates at risk, too.

Change.org have a petition up to deliver the untasty truth to NVIC – it caters to non-US residents from all over the world. Please sign it, tweet it or retweet this post, Facebook it, blog it and email it. These people need to be held accountable for their actions.

Safeminds defends treatments the FDA deemed “dangerously misleading”

18 Oct

The United States Food and Drug Administration (FDA) recently announced that they had sent warning letters to eight groups who were promoting chelation products without prescriptions and with unproven claims of efficacy.

Chelation is a mainstay of many alternative medical practitions, especially in autism. There is a hypothesis that autism is caused by mercury poisoning. Autism symptoms don’t look like mercury poisoning and multiple studies have been performed testing the hypothesis and shown no link. But the idea lives on. Autistics, mostly children, are subjected to chelation “therapy” to remove heavy metals from the body. After over a decade of this practice, there is still no demonstration that chelation does anything to help autistics. There are studies on Peruvian hamsters which are used to support the idea that autism is caused by mercury poisoning. No, seriously, one of the supports for the mercury/autism link is a study on Peruvian Hamsters. Just goes to show how tenuous the “science” backing chelation is.

Here is part of the FDA statement:

Federal regulators are warning eight companies to stop selling so called ‘chelation’ products that claim to treat a range of disorders from autism to Alzheimer’s disease.

The Food and Drug Administration (FDA) says the companies have not proven their products are safe and effective in treating autism spectrum disorder, cardiovascular disease, macular degeneration, Parkinson’s disease or any other serious illness. Some of the companies also claim their products can detect the presence of heavy metals in the body in an attempt to justify the need for chelation therapy.

One of the more vocal organizations promoting the mercury/autism “link” is a group called SafeMinds. So it isn’t a surprise that they would respond to the FDA warnings..

Here is the opening paragraph from the SafeMinds response:

The FDA issued a media release and held a press conference on over-the-counter chelating products. A recording of the press conference was made available this afternoon (recording available at 800-839-7073). FDA issued warning letters to 8 companies promoting over-the-counter nutritional supplements for chelation therapy (HERE). Chelation is a method of removing heavy metals from the body. The FDA warning has no bearing on prescription chelation drugs which are used under the supervision of medical professionals.

“Nutritional Supplements”? How does a chelator count as a “nutritional supplement”? The human body does not produce chemicals like DMSA which are used for chelation. SafeMinds is well aware of the falacy of the “nutritional supplement” argument after the recent debacle over the chelator turned “supplement” OSR, which had to be pulled from production.

So, SafeMinds starts downplaying the fact that chelators are drugs and, as such, should be regulated.

But they quickly change the tune and acknowledge that these are drugs: “The FDA warning has no bearing on prescription chelation drugs which are used under the supervision of medical professionals.”

As I read this, I had to ask myself “Why did SafeMinds chose such imprecise language?” Let me explain:

Assume a medical professional, say a chiropractor or a nutritionist, “supervises” my use of the prescription drug DMSA, but sells the drug to me without a prescription (as these professionals can not write prescriptions). That would fit into the SafeMinds interpretation, but is clearly not the intent of the FDA statement.

Here is an accurate statement: The FDA warning does not have bearing on the use of chelation drugs prescribed by and supervised by a medical professional.

Continuing with the SafeMinds statement:

In its press conference, the FDA implied that chelation products were being used by parents of children with autism without a doctor’s supervision, but on questioning by reporters, FDA representatives were unable to back up the claim with any evidence of use of OTC chelation products by autism parents or of their use without medical supervision. The FDA asserted that the OTC products being promoted were dangerous and could lead to kidney damage, dehydration and death. On questioning by reporters, the FDA admitted that it had received no reports of adverse reactions to the products or to chelation in general, other than 1 death 5 years ago which was due to a medical error and in which a prescription drug was used.

Note that SafeMinds chose their words carefully. They don’t state that the practice doesn’t occur. SafeMinds just states that the FDA didn’t have the evidence on hand of the “use of OTC chelation products by autism parents or of their use without medical supervision.”

Is Safeminds so out of touch with the online autism community that they can’t find groups promoting over-the-counter (OTC) chelators by autism families? The practice is common. Surely SafeMinds members peruse the exhibitor booths at the parent-conventions (like Autism One).

Google search: “how to buy DMSA without a prescription”. Lot’s of hits.

Here is hit #2: dmsachelation.com/autism/. Pretty clear they are targeting autism treatment there, just from the URL. The blurb on Google for this site? “This page IS intended to show you where to buy DMSA without a prescription. You can get DMSA prescribed, however the cost will range from $2-3 per pill. …”

I didn’t capitalize “IS” in that statement, they did. They wanted to emphasize that one could buy chelators without a prescription.

SafeMinds states that the FDA has received no reports of adverse events from chelation in general. I find this odd. The FDA must not follow online autism parent groups such as those on Yahoo. The FDA must not have read transcripts of the Omnibus Autism Proceeding, which included a description of a child who regressed after being given chelation therapy (under the watchful eye of a prominent alt-med doctor). The FDA must not have performed a google search on chelation deaths with site set to CDC.gov.

First hit, “Deaths Associated with Hypocalcemia from Chelation Therapy — Texas, Pennsylvania, and Oregon, 2003–2005“.

When it comes to the question of “why” adverse events are not commonly reported I am again reminded of the OSR fiasco. The company that sold OSR specifically told their clientele to contact the company in case of adverse reactions. No mention was made of contacting the FDA (which can be done here). I guess I could search the websites of the groups that promote OTC chelators to see if they inform their clients of the ability to report their drug/supplements to the FDA. Somehow I feel confident that I would be able to find groups (possibly many or most) do not give that information.

SafeMinds posted their statement on the blog they sponsor, The Age of Autism. Another sponsor of that blog is Lee Silsby, a compounding pharmacy. They list chelators such as DMSA and EDTA under the category “autism treatments” (Specialties | Autism Treatments | Transdermal DMSA Cream, or Specialties | Autism Treatments | EDTA (calcium)). Not under “heavy metal poisoning” treatments, autism treatments.

The Autism Research Institute, a group which promotes much in the way of alternative medicine as therapies for autism, has a chart that is often used to promote chelation. In their survey, they claimed that over 70% of parents reported that their child got better with chelation. The survey has been often criticized as being unscientific and very biased. Even with this biased sample, 3% of parents reported that their child “got worse” with chelation.

A couple side notes are worth mentioning. First, in that survey the ARI list chelation under “Biomedical/Non-Drug/Supplements”. Non drug? Supplement? I doubt the FDA will agree. Second, the ARI survey lists secretin therapy as beneficial for autism. Secretin hit the news in the 1990’s as a potential autism therapy and has since been shown to be no more effective than a placebo. The survey is very, very biased towards “biomedical” treatments.

Surely SafeMinds is aware of this survey. As in, definitely they are aware of it. Just as Safeminds are certainly aware of the child in the Omnibus proceeding who suffered after chelation. But SafeMinds pretend as though there are no adverse reactions. It is disingenuous, to say the least.

SafeMinds ends their statement with this paragraph:

SafeMinds agrees with the FDA that products being promoted as drugs and biologics should have thorough and unbiased assessments for safety and that parents should work with their healthcare professionals when considering health interventions. SafeMinds feels that FDA has tried to cast autism parents in a negative light without any supporting evidence, by implying that autism parents were giving their children dangerous products without medical oversight. Only on questioning by the media did the FDA have to back off from its wild claims. SafeMinds feels the FDA owes the autism community an apology.

Basically, SafeMinds have taken the Human Shield defense. Rather than actually discuss the facts, SafeMinds attacks the FDA for “wild claims” and claims that the FDA owes the autism community an apology.

From the perspective of this autism parent I would say, yes, the FDA owes us an apology: for taking so damned long to address this issue. The abuse of chelation as a “treatment” for autism has been going on for many years. It is about time that the FDA cracked down and made the “wild claim” that a prescription drug should be given by perscription.

Heck, the FDA isn’t even making the “wild claim” that toxicology treatments should be performed by toxicologists. Just someone with a prescription pad.

Why isn’t SafeMinds telling autism families to seek out medical toxicologists to test and treat heavy metal poisoning? The answer is painfully clear. The methods of diagnosis and treatment that groups like SafeMinds promote do not compare to the methods used by those trained specifically to treat heavy metal intoxication.

Should make one pause to wonder.

No association between XMRV and autism?

15 Oct

Recently there has been growing interest in XMRV (Xenotropic murine leukemia virus-related virus) and autism. I haven’t discussed it here on LeftBrainRightBrain as it has been very preliminary.

Well, it looks like I may not ever get into this story in depth as XMRV appears to not be associated with autism.

From ERV at ScienceBlogs, XMRV and Autism: Best conflict of interest EVAH! I learned of this new paper:

PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism

Here is the abstract.

Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus implicated in prostate cancer and chronic fatigue syndrome (CFS). Press releases have suggested that it could contribute to autism spectrum disorder (ASD). In this study we used two PCR assays and one antibody assay to screen 25 blood samples from autistic children born to mothers with CFS and from 20 mixed controls including family members of the children assayed, people with fibromyalgia and people with chronic Lyme disease. Using a real-time PCR assay, we screened an additional 48 South Carolina autism disorder samples, 96 Italian ASD)samples, 61 South Carolina ASD samples and 184 healthy controls. Despite having the ability to detect low copy number XMRV DNA in a large background of cellular DNA, none of the PCR assays found any evidence of XMRV infection in blood cells from patients or controls. Further, no anti-XMRV antibodies were detected, ruling out possible low level or abortive infections in blood or in other reservoirs. These results imply that XMRV is not associated with autism.

“These results imply that XMRV is not associated with autism.”

ERV noted this paragraph of the paper:

In an interview given on the same day as the Lombardi publication, Dr Mikovits stated that they had found XMRV in a ‘significant number’ of autism spectrum disorder (ASD) samples and speculated that ‘this might even explain why vaccines lead to autism in some children’ [6]. Shortly thereafter, widely circulated articles appeared, containing non-peer reviewed data with reports that XMRV may be present in ?40% of people with autism [7]. Given the recent controversy over the connection between ASD and the MMR (measles, mumps, rubella) vaccine, a scientific evaluation of these statements is important [8,9].

Translation (via ERV):

Mikovits started talking to the media/patients/parents before she had any published science to back up her claims. She increased fear of vaccines. She still hasnt published anything. So I guess we are going to clean up this mess for her.

Also, ERV points out one of the most interesting competing interests statements in a paper:

COMPETING INTERESTS
BCS and RAG are employees of Cooperative Diagnostics. Cooperative Diagnostics is a commercial enterprise that owns the rights to the XMRV real-time PCR assay described in this manuscript, in addition to the Master Mix that was used. Publication of these results may well reduce the potential market that Cooperative Diagnostics could reach with its XMRV assay.

Yes, the authors are from a company which has rights to XMRV tests. If XMRV is not associated with autism, this company stands to make less money in the future.

Ironically, David Kirby is scheduled to present “breaking news” at an upcoming workshop in November:

Breakthrough News: David Kirby will discuss the recent research by Judy Mikovitz of the University of Nevada. Dr. Mikovitz helped discover that XMRV retrovirus was present in 95% of people with chronic fatigue, and she also found in 40% of a small sample of ASD kids. So far, virtually all of the kids whose moms have XMRV and chronic fatigue also have the XMRV virus.

Somehow I doubt the facts in this new study will divert Mr. Kirby from his “breaking news”. Facts have failed to stop him in the past.

FDA: Chelation not proven safe or effective in treating autism

14 Oct

Chelation is a process whereby metals are removed from the body using a drug, a chemical which binds to the metals and allows them to be excreted. Because of the incorrect notion that autism is caused by mercury or is a “novel” form of mercury poisoning, chelation is one of the more common alternative medical therapies applied to autistics.

The FDA has recently issued a warning to many of those who market unapproved chelators. Two articles appear on the FDA website today:

FDA Tightens Reins on Unapproved ‘Chelation’ Drugs

and a press release

FDA issues warnings to marketers of unapproved ‘chelation’ products.

They have also issued a printer-friendly pdf: FDA chelation warning pdf

From that pdf:

Federal regulators are warning eight companies to stop selling so called ‘chelation’ products that claim to treat a range of disorders from autism to Alzheimer’s disease by removing toxic metals from the body.

The Food and Drug Administration (FDA) says the companies have not proven their products are safe and effective in treating autism spectrum disorder, cardiovascular disease, macular degeneration, Parkinson’s disease or any other serious illness. Some of the companies also claim their products can detect the presence of heavy metals in the body in an attempt to justify the need for chelation therapy.

The groups that have been warned are:

• World Health Products, LLC: Detoxamin
Oral, Detoxamin Suppositories, and the
Metal Detector test kit
• Hormonal Health, LLC and World Health
Products, LLC: Kelatox Suppositories,
and the METALDETECTOR Instant Toxic
Metals Test
• Evenbetternow, LLC: Kids Chelat Heavy
Metal Chelator, Bio-Chelat Heavy Metal
Chelator, Behavior Balance DMG Liquid,
AlkaLife Alkaline Drops, NutriBiotic
Grapefruit Seed Extract, Natur-Leaf,
Kids Clear Detoxifying Clay Baths, EBN
Detoxifying Bentonite Clay, and the
Heavy Metal Screen Test
• Maxam Nutraceutics/Maxam Laboratories:
PCA-Rx, PC3x, AFX, AD-Rx, AN-Rx,
Anavone, AV-Rx, BioGuard, BSAID, CF-Rx,
CreOcell, Dermatotropin, Endotropin,
GTF-Rx, IM-Rx, Keto-Plex, Natural Passion,
NG-Rx, NX-Rx, OR-Rx, Oxy-Charge,
PN-Rx, Ultra-AV, Ultra Pure Yohimbe, and
the Heavy Metal Screening Test
• Cardio Renew, Inc: CardioRenew and
CardioRestore
• Artery Health Institute, LLC: Advanced
Formula EDTA Oral Chelation
• Longevity Plus: Beyond Chelation
Improved, EndoKinase, Viral Defense,
Wobenzym-N
• Dr. Rhonda Henry: Cardio

I wonder how the FDA chose these groups for the first round of warnings. I also wonder if/when there will be more warning letters.

Also from the FDA pdf:

FDA says consumers should avoid nonprescription products offered for chelation or detoxification. FDA-approved chelating agents are available by prescription only and are approved for use in specific indications such as the treatment of lead poisoning and iron overload. The agency says even the prescription medications carry significant risks, and they should only be used with medical supervision.

I don’t know why the FDA has taken so long to step in and take action. Chelation has been going on for years, and has never had a sound basis in science or even a good rationalization for the treatment of autism.

Trine Tsuderous has an article on the Los Angeles Times website, FDA warns about treatments for autism, heart disease.

Sibling Recurrence and the Genetic Epidemiology of Autism

5 Oct

As if to follow up on the Social Demographic Change and Autism paper we recently discussed here on LeftBrainRightBrain, a new paper on autism recurrence risk in families came out today. Sibling Recurrence and the Genetic Epidemiology of Autism is from a team from the Kennedy Krieger Institute at the Johns Hopkins University. From the abstract I would guess that the study uses the IAN Database.

The authors find about 11% recurrence risk, much higehr than the prevalence of autism (about 1%) and quite similar to that of the Bearman group. Further, the Kennedy Kreiger team find that about 20% of non-autistic siblings have a history of language delay.

Am J Psychiatry. 2010 Oct 1. [Epub ahead of print]
Sibling Recurrence and the Genetic Epidemiology of Autism.

Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P.

Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; the Center for Autism, Cleveland Clinic, Cleveland; and the Kennedy Krieger Institute, Medical Informatics, Baltimore.
Abstract

Objective: Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings. Method: The authors report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register, with at least one child clinically affected by an autism spectrum disorder and at least one full biological sibling. Results: A traditionally defined autism spectrum disorder in an additional child occurred in 10.9% of the families. An additional 20% of nonautism-affected siblings had a history of language delay, one-half of whom exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale supported previously reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multipleincidence families and a relative absence of quantitative autistic traits among siblings in single-incidence families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts. Conclusions: These data suggest that, depending on how it is defined, sibling recurrence in autism spectrum disorder may exceed previously published estimates and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism and advance current understanding of the genetic epidemiology of autism spectrum conditions.

Social Demographic Change and Autism: part 2

3 Oct

Prof. Peter Bearman’s group is studying the causes for the rise in autism prevalence, using data from the California Department of Developmental Services. I recently wrote a rather long introduction to their recent paper, Social Demographic Change and Autism.

The study abstract is here:

Social Demographic Change and Autism
Liu K, Zerubavel N, Bearman P.

Abstract

Parental age at child’s birth–which has increased for U.S. children in the 1992-2000 birth cohorts–is strongly associated with an increased risk of autism. By turning a social demographic lens on the historical patterning of concordance among twin pairs, we identify a central mechanism for this association: de novo mutations, which are deletions, insertions, and duplications of DNA in the germ cells that are not present in the parents’ DNA. Along the way, we show that a demographic eye on the rising prevalence of autism leads to three major discoveries. First, the estimated heritability of autism has been dramatically overstated. Second, heritability estimates can change over remarkably short periods of time because of increases in germ cell mutations. Third, social demographic change can yield genetic changes that, at the population level, combine to contribute to the increased prevalence of autism.

They start by noting their group’s previous work which showed an increased risk for autism based on both maternal and paternal age.

There is a strong relationship between parental age and autism. The one study (King et al. 2009) that decomposes maternal and paternal age—and confounding cohort effects— identifies maternal age as riskier than paternal age (using the California data deployed in this analysis).

Relative risks were as high as 1.8. These are not as high as the increased risk for Down Syndrome, which can be 10x higher in older mothers, but it is still a notable effect.

The authors note that parental age has increased notably during the 1990’s, the same time that the “autism epidemic” started.

… the proportion of children born whose parents were age 35 or older at birth increased rapidly: from 24.3% in 1992 to 36.2% in 2000.

Many factors have been identified as correlated to the autism increase. Basically anything that increased over the 1990’s could be argued to be correlated with an increase in autism prevalence. Correlation is not causation, as we hear over and over. One must go beyond correlation in order to claim that there is a real effect.

And Prof. Bearman’s group does go beyond correlation. They look at autism in twins and siblings and show that (1) the concordance is much lower than has been previously reported and (2) the concordance is changing with time. They go into detail on the methods in the paper, including how to determine how many twins were “identical” (monozygotic or MZ) vs. fraternal dizygotic or DZ). Here is the table showing the concordance for twins and sibling pairs from the paper, Casewise and Pairwise concordance numbers are given.

Casewise concordance (Pcw) measures the probability that a co-twin will be affected (with a given disorder), given that the other twin is affected. Pairwise concordance (Ppw) measures the proportion of concordant (both twins are affected) pairs in all pairs with at least one twin who is affected.

Pairwise concordance is what most people think of as concordance.

The pairwise concordance is 40% for MZ (identical) male twins and 50% for female twins. Much lower than the higher values from previous, smaller studies which claimed 36-90% concordance. From the paper from Prof. Bearman’s group:

The Evidence for High Heritability of Autism
To date, the strongest evidence supporting the idea that autism is a genetic disorder arises from twin and family studies. Previous twin studies on full syndrome autism have reported high pairwise concordance rates in identical (MZ) twins (36%–96%) and low concordance rates in fraternal (DZ) twin pairs (0%–31%) (Bailey et al. 1995; Folstein and Rutter 1977; Ritvo et al. 1985; Steffenburg et al. 1989). Because MZ twins share 100% of their genes while DZ twins share only around 50%, a large difference between MZ and DZ concordance rates is regarded as strong evidence for genetic infl uences. The recurrence risk of autism in siblings is reported to range from 3%–9%, which is much higher than the population rate of 10 in 10,000 children (Baird and August 1985; Bolton et al. 1994; Piven et al. 1990; Ritvo et al. 1989).3 Relatives of a child with autism are also more likely to have broadly defined autism spectrum traits than controls (Szatmari et al. 2000).

Low concordance is consistent with another recent study, Genetic variance for autism screening items in an unselected sample of toddler-age twins, from Prof. Goldsmith’s group at U. Wisconsin. The abstract is below:

OBJECTIVE: Twin and family studies of autistic traits and of cases diagnosed with autism suggest high heritability; however, the heritability of autistic traits in toddlers has not been investigated. Therefore, this study’s goals were (1) to screen a statewide twin population using items similar to the six critical social and communication items widely used for autism screening in toddlers (Modified Checklist for Autism in Toddlers); (2) to assess the endorsement rates of these items in a general population; and (3) to determine their heritability.

METHOD: Participants composed a statewide, unselected twin population. Screening items were administered to mothers of 1,211 pairs of twins between 2 and 3 years of age. Twin similarity was calculated via concordance rates and tetrachoric and intraclass correlations, and the contribution of genetic and environmental factors was estimated with single-threshold ordinal models.

RESULTS: The population-based twin sample generated endorsement rates on the analogs of the six critical items similar to those reported by the scale’s authors, which they used to determine an autism threshold. Current twin similarity and model-fitting analyses also used this threshold. Casewise concordance rates for monozygotic (43%) and dizygotic (20%) twins suggested moderate heritability of these early autism indicators in the general population. Variance component estimates from model-fitting also suggested moderate heritability of categorical scores.

CONCLUSIONS: Autism screener scores are moderately heritable in 2- to 3-year-old twin children from a population-based twin panel. Inferences about sex differences are limited by the scarcity of females who scored above the threshold on the toddler-age screener.

Back to Prof. Bearman’s study: their analysis went deeper, including measures of the pairwise concordance for non “identical” twins. Opposite sex twins have a 10% concordance, and same sex twins (dizygotic) have 20% concordance. That gender difference in concordance is quite notable.

The risk of having an autistic child is much higher if one already has an autistic child. The recurrance risk is about 10% for full siblings, 3% for half siblings. These values are quite high considering that the autism (not ASD, but autism) prevalence is less than 1%. The recurrence risk is much higher for siblings of an autistic female than autistic male. Male siblings of a female “proband” have a recurrence risk of 18%. Female siblings of a male “proband” have much lower recurrence risk of 5%.

Prof. Bearman’s group has done what may be a first in concordance studies: analyzed data as a function of birth year. “Temperal concordance”. I.e. they ask the question, does the concordance change with time? The answer, yes.

Here are panels (A) and (B) from Figure 1 of the paper.

Panel (A) shows casewise temporal concordance. Concordance increases for single-sex (SS) twins, and decreases for other-sex (OS) twins during the 1990’s. The authors note this is consistent with a de novo mutation mechanism for increased risk for autism. Panel (B) shows that the average age for the twin parents is also increasing over this time period. From the paper:

In panel B, we report change in mean parental age at twin births, which increases steadily during the same period. Recall that because MZ twins are developed from a single pair of matched egg and sperm cells, any de novo mutations will be found in both twins. In contrast, DZ twins develop from two distinct pairs of egg and sperm cells. Because de novo mutations are rare events, the chance that both DZ twins will share the same de novo mutation is extremely low. If de novo mutations have an increasing causal share in the etiology of autism over time, we should expect an increase in the difference between MZ and DZ concordance rates. One mechanism that accounts for de novo mutations’ increasing share of autism etiology is the rise in parental age over our study period, which is likely to lead to increased mutation rates.

One question that naturally arises in regards to multiple births is the use of assisted reproduction technology (ART). The authors discuss this:

Although the genetic influence on autism has been overestimated, it has increased over time due to non-allelic mechanisms. Although the human gene pool does not change substantially over one or two generations, de novo germ-line mutation rates are much more susceptible to rapid social and/or environmental changes (such as rising parental age), and thus can explain the increase in the heritability of autism. Of importance is the fact that although age of parents at birth of twins was signifi cantly higher in 2000 than in 1992, age of parents at the birth of their second-born did not increase over the same period. Thus, the difference between the trends of OS twin concordance and full-sibling recurrence risk may be associated with age of parents. Since the use of assisted reproductive technologies (ART) is associated with the age of parents and has increased radically over the same time period, ART may be implicated in the increased prevalence of autism. Our data show that the increase in the percentage of children with autism born in multiple births (from 3.6% in 1992 to 5.7% in 2000) exceeded that of the percentage of multiple births in all births in California (from 2.1% in 1992 to 2.9% in 2000). This implication requires future investigation.

The risk of autism is higher with multiple births and increased at a greater rate than the percentage of multiple births in general.

The authors discuss the possibility of prenatal exposures to infection or toxicant or a gene/environment interaction might follow the same trends they observe:

It remains possible that other factors have contributed to the diverging trends in the SS and OS concordance. A virus or a toxicant experienced in utero could yield the results that we observe. Specifically, an increasingly prevalent virus (or toxicant) associated with a small risk of autism would lead to increasing concordance of SS twins (who often share the same placenta) and decreasing concordance of OS twins. Similarly, interactions between genes and an increasingly common environmental trigger could also generate the same pattern. However, we believe that an increase of de novo mutations attributable to rising parental age is more parsimonious given the documented rise in parental age, recent findings that link de novo mutations and autism, and the observed associations between concordance rates and parental age reported in this article.

The authors address one concern that I had in reading the paper: what if some change in the way children are qualified for regional center services changed the characteristics of their population. Or, to put it more simply, are the autistics in 2000 really comparable to those in 1990? Regional center data show a decreasing percentage of children also in the mental retardation and epilepsy categories. Could this have an effect on their results? From the paper:

The temporal concordance trend reported in this article is not predicted by a diagnostic expansion theory. If ascertainment and surveillance dynamics rest behind the increase in SS concordance, we would expect to observe increasing rather than decreasing concordance for OS twin pairs over time. The observation of decreasing concordance over time in OS twins challenges the idea that the results we observe are an artifact of reduction of error in diagnosis as a consequence of enhanced surveillance or clearer understanding of diagnostic markers. First, there is no evidence that diagnostic errors have been reduced; second, if this were the case, we should observe the same effect across all pair types. Finally, increasing ascertainment and surveillance would predict heightened recurrence risk for siblings over time. We do not observe any increase in such risk (chi-square statistics of linear trends in proportion = 1.613; p = .204).

The authors’ concluding paragraph is:

For social scientists, there are three important discoveries. First, we show that a sociological eye on the role of genetics yields the insight that de novo mutations may play a signifi cant role in autism etiology. Only by observing changing patterns of concordance over time—that is, historicizing genetic influences rather than essentializing them—could we find evidence of a new causal mechanism underlying autism. Second, by working with a large population-based data set, versus small clinical samples, we have been able to properly estimate the true heritability of autism. These estimates show that autism is far less heritable than previously thought and consequently, explanations for the precipitous increase in prevalence must turn toward environmental and social dynamics often ignored by the scientific research community. Third, we show that the identification of the mechanisms by which social processes operating at the macro level—in this case, increases in parental age—“get under the skin” and shape health outcomes is a proper social science activity.

This study has the possibility to have a major impact on autism causation research. I would not be surprised at all if this ends up as one of the papers highlighted by the IACC for the year. I’m certain that this paper will be brought up in online discussions for some time to come, what with the very different estimate of twin concordance than previously quoted.

Social Demographic Change and Autism: part 1

3 Oct

I’ve been meaning to blog this for a long time. Ever since it came online, which was months ago. I’ve wanted to do a good job on this paper and so I’ve kept putting it off while I wait for the time to really dig into it. Kev’s recent post about Prof. Bearman got me thinking it is time to get this out. I knew this would be long and it has grown longer than I expected, so I have split the post up. Here are some introductory thoughts. Much as people like to paint me as being in the “genetics” camp, it isn’t really my interest. Someone like Prometheus would do a far better job on an intro and discussion that I can. But in Prom’s absence, I will say what I can.

Prof. Peter Bearman is a researcher at Columbia University. His team has taken a very careful look at the California Department of Developmental Services (CDDS) data and combined this with California birth record data and come up with what are likely some of the best papers to come from those data. The CDDS provides services to the developmentally disabled in California through a series of “Regional Centers”, which are private corporations which administer the state’s funding through largely non-governmental agencies in the state. They have records on the people (consumers) whom they have served over the years and these data include information on how the consumers qualify for services.

There are five eligibility categories for regional center support:

1) Mental Retardation: Significant deficits in general intellectual functioning (generally an IQ of 70 or below) and significant deficits in adaptive functioning.

2) Cerebral Palsy: A neurological condition occurring from birth or early infancy resulting in an inability to voluntarily control muscular activity, and resulting in significant deficits in motor adaptive functioning and or cognitive abilities.

3) Epilepsy: A disorder of the central nervous system in which the major symptoms are seizures. Eligibility is based on a seizure disorder that is uncontrolled or poorly controlled , despite medical compliance and medical intervention.

4) Autism: A syndrome characterized by impairment in social interaction (withdrawal, failure to engage in interaction with peers or adults), delays in both verbal and nonverbal communication skills, deficits in cognitive skills, and impairment in the ability to engage in make-believe play. Individuals may engage in repetitive activities or a limited repertoire of activities.

5) Fifth Condition: This category includes disabling conditions found to be closely related to mental retardation or requiring treatment similar to that required for individuals with mental retardation.

As a side note, a lot of people forget the “Fifth Condition” category. People will say that people with Asperger Syndrome or PDD-NOS don’t qualify for Regional Center services. Well, they don’t under the “autism” category, but they can under the fifth condition if they meet the requirements for a “substantial disability”. But, I am digressing.

The CDDS data have been extensively used to demonstrate the very large increase in autism prevalence that has occurred over the last 20-30 years.
Prof. Bearman’s group has studied the CDDS data and found that some of the increase can be found to attributed to factors such as changes in the way people are diagnosed (diagnostic accretion) and lower ages of identification.

In a recent paper, Social Demographic Change and Autism, Prof. Bearman’s group argues that about 11% of the rise in autism prevalence can be attributed to genetics.

Sorry to give away the conclusion so early but this is going to be long and I know a lot of people won’t read it all.

Genetics is a hot-button issue with a lot of people in the online autism community. Sometimes people will divide the world into two camps: those who believe autism is caused by vaccines and those who believe autism is caused by genetics. It is a major oversimplification but it happens.

Another oversimplification is to confuse genetics and heritability. As in, “I’m not autistic and my wife isn’t autistic, genetics doesn’t account for my kid being autistic”. This is wrong on so many counts. Heritability implies genetics, but not all genetics is heritable.

In high school or even earlier you probably learned about a monk and pea plants and later studies on fruit flies and the color of their eyes. This is Mendelian inheritance. You learned that some traits are recessive and some are dominant.

From this framework, you can’t get a genetic epidemic.

Whenever the argument about genes and changing prevalence comes up, you can be sure someone will eventually bring up Down Syndrome. Down Syndrome is a developmental disability (possibly an example of the sort that comprise the “fifth category” in the DDS). Down Syndrome is genetic. Not always Mendelian inheritance genetic, but genetic all the same.

The risk factors for having a child with Down Syndrome are

1) Advancing maternal age. A woman’s chances of giving birth to a child with Down syndrome increase with age because older eggs have a greater risk of improper chromosome division. By age 35, a woman’s risk of conceiving a child with Down syndrome is 1 in 400. By age 45, the risk is 1 in 35. However, most children with Down syndrome are actually born to women under age 35 because younger women have far more babies.
2) Having had one child with Down syndrome. Typically, a woman who has one child with Down syndrome has about a 1 percent chance of having another child with Down syndrome.
3) Being carriers of the genetic translocation for Down syndrome. Both men and women can pass the genetic translocation for Down syndrome on to their children.

Part 2 and 3 are what we usually think of as “genetic”, as in “Mendalian”. But what about (1) advancing maternal age? A 10 times greater risk for older mothers? Keep in mind, there is a clear genetic difference behind Down Syndrome.

In humans, the egg cells and sperm cells have 23 chromosomes. The rest of your cells normally contain 23 pairs of chromosomes — one from your father and one from your mother. Kids with Down syndrome usually have three copies of chromosome 21 — called trisomy 21 — instead of two copies.

There is a difference, some might call it an error, in the genetic sequence which leads to Down Syndrome. The parents don’t need to have it. It can be genetic and not heritable. Or, at least, not heritable in the way most people think.

Parental age is increasing. We would be seeing an epidemic of Down Syndrome if it weren’t for the genetic test that is available and offered to most pregnant women.

There are already studies out discussing increased risk for having an autistic child with parental age. If parental age is increasing (and it is), why don’t we see an epidemic of autism from this?

Add to this the recent study from the Autism Genome Project (which came out after this paper by Prof. Bearman’s group). That study, and others, are showing that rather than an autism “gene”, that copy number variations (CNVs) may be one source of genetic risk for autism. These are not heritable in the usual sense as usually they exist in the child and not the parent.

According to Prof. Bearman, we are seeing it. It accounts for about 11% of the increase in autism prevalence in the CDDS data. It is a big effect, but small compared to the other factors going on (the other 89%). So without a careful look, one can’t show it.

Prof. Bearman’s group *is* taking a careful look. The result is their paper Social Demographic Change and Autism. There are a lot of very interesting results, like twin concordance being much smaller than has been previously reported. Another recent paper confirms that. Strangely, no one seems to have noticed.

I’ll try to rectify that in the next installment when we look closer at the paper. Until then, here is the abstract:

Parental age at child’s birth—which has increased for U.S. children in the 1992-2000 birth cohorts—is strongly associated with an increased risk of autism. By turning a social demographic lens on the historical patterning of concordance among twin pairs, we identify a central mechanism for this association: de novo mutations, which are deletions, insertions, and duplications of DNA in the germ cells that are not present in the parents’ DNA. Along the way, we show that a demographic eye on the rising prevalence of autism leads to three major discoveries. First, the estimated heritability of autism has been dramatically overstated. Second, heritability estimates can change over remarkably short periods of time because of increases in germ cell mutations. Third, social demographic change can yield genetic changes that, at the population level, combine to contribute to the increased prevalence of autism

Is the end of the Omnibus Autism Proceeding near?

2 Oct

The Omnibus Autism Proceeding (OAP or omnibus) is the way the Court of Federal Claims (vaccine court) has been handling the now 5,000+ claims submitted for autism as a vaccine injury. The Omnibus started officially in July of 2002 with Autism General Order #1. Along the way it was decided that the best way to handle the large number of claims was using “test cases”. Three test cases were heard for each of two “causation theories”. The idea was that “general causation” arguments could be made once, and very thoroughly, and the other cases could be decided on the outcome.

The first causation theory was that the MMR vaccine in combination with thimerosal could result in autism. The test cases for this theory were those of Michelle Cedillo, William Yates Hazelhurst and Colten Snyder. Attorneys for the families presented evidence for a mechanism where thimerosal was proposed to reduce the immune response and the MMR vaccine led to a persistent measles infection which, again as proposed, led to symptoms of autism. In all three cases the special masters (judges) ruled against the petitioner families. They found that the evidence did not support the mechanism proposed.

The second causation theory held that thimerosal in vaccines could result in autism. Three test cases were presented, again with individual and general causation evidence. The test cases, Jordan King and William Meade, and Colin Dwyer were heard. Their attorneys argued that mercury from the thimerosal in the vaccines accumulated in the brains and resulted in neuroinflammation which, in turn, resulted in autism. As with the MMR case, the special masters ruled against the petitioner families.

To put it simply: all the data and all the experts that could be put together to support the idea that vaccines cause autism weren’t persuasive. They came up with two stories (MMR and thimerosal) and neither story made a case that was even close (the special master’s word).

Some of the petioners appealed. Some appealed to multiple levels. The appeals were denied.

The Court recently issued an update letter. I quote part of it below:

As described above in part I of this Update, all of the court rulings in the six test cases described above have found no causal link between autism and MMR vaccines and/or thimerosal containing vaccines. Further, the PSC has informed the special masters that no additional OAP test cases are contemplated.

Therefore, the Office of Special Masters has begun discussions with members of the petitioners’ bar and respondent’s counsel about how best to conclude the approximately 4,700 autism cases remaining open on the court’s docket. To aid in that process, some petitioners’ counsel have contacted all of their OAP clients to advise them of the results in the test cases and to recommend a course of action with regard to their claims. Additionally, all petitioners who are not represented by counsel have been ordered to inform the court either that they wish to dismiss their claim or that they intend to proceed with their case. For petitioners who wish to continue with their claim, orders to identify a theory of causation, produce an expert report, and file additional evidence will follow. Petitioners’ counsel who have not yet done so are encouraged to contact their clients and determine how their clients wish to proceed.

The issue of attorneys’ fees and costs for petitioners’ counsel is part of the discussion about how to conclude proceedings on the OAP petitions. Mediation efforts are underway to develop methods to resolve the fees and costs issues, and a report on the progress in these talks is expected at the October judicial conference.

The special masters are assuming that no one will go forward with the MMR and thimerosal theories. Since those theories don’t hold up in court, it seems a good assumption.

Petitioners can still go forward as individual cases, as in any non-omnibus case. They will need to submit records and a theory of causation and support that theory in hearing.

The PSC (petitioner’s steering committee, a group of lawyers which has managed the Omnibus from petitioner’s side) has decided that no additional OAP (Omnibus) test cases are planned.

This is very important. They have no other theories to present. They don’t plan to present “too many too soon”. They don’t plan to present a Wakefield-like theory of persistent measles infections leading to “leaky guts”. They don’t plan to present a “mitochondrial autism” theory.

This last bit is very important. The Hannah Poling case made a lot of news when it was leaked that the government had conceded her case as a table-injury MMR encephalopathy. She was supposed to be one of the three thimerosal test cases. At the time of the concession and since, it was asserted that her case was “not rare” and that the attorneys were prepared to go ahead with the mitochondrial disorder story. It would appear that there are not many (if any) other “Hannah Poling” cases out there. There is at least one family pursuing a variation of the mitochondrial disorder theory. Alexander Krakow was scheduled to be a test case for the thimerosal theory and his family pulled out of the Omnibus to pursue the mitochondrial theory.

While there may be a case or two that we hear about from here on out, it appears that the Omnibus, the “class action” type phase, is over.

Katie Wright demonstrates AoA mentality

30 Sep

Over at the Clown Blog, Katie Wright pens a sulky screed targeting Peter Bearman. Lets go through it.

Dr. Peter Bearman, a professor of sociology at Columbia University, recently released a research paper alleging that half of the meteoric rise in ASD cases is an artifact. You know- “better diagnosis” and “greater awareness.” A blind, non-medical professional, could have diagnosed my son. Nevertheless in the case of HF ASD and aspergers (which comprise a small % of overall ASD) certainly greater awareness has played a role in the increasing number of those diagnoses. Still- 50%? Ridiculous.

And why ridiculous? Well….just because. Wright offers no evidence to counteract Bearman’s. No science is referenced to challenge Bearman’s work. It simply is ridiculous apparently. One can almost hear the foot stomp of a poor little rich girl out of her league intellectually.

After Dr. Bearman concludes that 50% of the increase cannot be attributed to greater awareness Insel asks what Bearman believes is driving the other 50%. Bearman answers: “genes, old parents and possibly a virus.” This is the best he has got? The NIH gave this guy millions to come with that?

Well no Katie, thats not what the NIH gave him his research money for. According to _you_ Insel asked Bearman what he _believed_ was driving the other 50%. He gave his answer as to what he _believed_ . But these beliefs were just that – beliefs. He presented the science he had done and then shut up on the evidence and opined and on what he was asked to opine on by Insel.

And even his opinion, his beliefs, are rooted in science. There _is_ a genetic component to autism, thats simply a fact. There _is_ research that links ASD to older parents. Katie Wright’s beliefs revolve around one extremely unscientific thing. Vaccines.

Yes, Bearman does acknowledge the possible role of some kind of toxin. Bearman is not sure what that toxin is but he is sure what it isn’t. Take a guess.

See what I mean. If it ain’t a vaccine, it ain’t worth considering according to Katie Wright.

…unbelievably Bearman says: “it isn’t autism that parents are worried about. They know they can deal with that, they know they can help their child, (and he would know this a non parent of an ASD child?) but it is autism organizations scaring parents!” I had no idea that a bunch of stay at home Moms with no money, no federal backing, no million dollar grants- who are already busy parenting autistic kids- have this kind of extraordinary power! Wow, what’s next for us? Ending the recession, solving the mortgage crisis, creating electric cars?

And hot damn Katie Wright, guess what? In my opinion he _is_ right! I’m not scared of autism. I’m scared of one note zealots stealing away research monies, scaring away legitimate researchers with their threats of violence and scaring the public into believing that autism is some kind of tsunami of evil ready to engulf them all in a tide of social security claims.

As for Katie Wright personally, it makes me sick to think of this little rich girl, who’s children will want for nothing, playing the ‘poor little me’ card. There are families out there struggling to get by on a day to day basis and she has the temerity to liken herself to a ‘stay at home mom’. Feh.

As far as blaming the parents for the national crisis of confidence in vaccine safety- grow up Dr. Bearman. The problem is the problem- not people talking about the problem.

Nice quote from that intellectual giant Jim Carrey there. Oh and guess what Katie Wright? You and people like you *are the problem* . Whilst you play offended at legitimate science, there’s a whooping cough outbreak in California that is killing children. You do know that don’t you Katie Wright?

Here’s what you need to do Katie Wright. You need to accept the fact that the science is against you. You need to accept the fact that you are a small scaremongering minority of the autism community. Sounding off about stuff that you clearly have absolutely zero knowledge about (science) makes you look foolish and all it does is show you to be frightened. You are behind the times. Get out of the way of progress.

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