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.

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7 Responses to “Social Demographic Change and Autism: part 2”

  1. Joseph October 4, 2010 at 15:38 #

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

    Sure, but that’s essentially coincidental. Its impact can’t be more than a small fraction of the observed rise in diagnoses. Parental age was increasing before the 1990s.

    Or to put it another way, if parental age had been constant all along, we’d still be having the same arguments.

  2. passionlessDrone October 4, 2010 at 16:01 #

    Hi Sullivan –

    Very nice postings. I had a couple of thoughts:

    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%.

    Hm. What does this mean in regards to the discussion had on this board a few weeks ago regarding the Y chromosome and potential for this to be a genetic blindspot that could be responsible for our male to female ratio of ASD? Do we have risk ratios for our other options; i.e., female siblings of a female proband, and male siblings of a male probrand available?

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

    Curious. I thought that it made sense from an in utero ‘competetion’ standpoint that multiple births could be a risk factor for autism; it seems that the number of things that can go just a twinge wrong during development with butterfly effects on the brain are so large that having to share nutrients, or having an additional stressor on the mother, was a logical risk factor.

    This has been studied a couple of times with very different results. Specifically, Excess of twins among affected sibling pairs with autism: implications for the etiology of autism reported a wild bias in twins for an autism diagnosis, and subsequently Increased Rate of Twins among Affected Sibling Pairs with Autism also reported increased risks. However, other studies were either inconclusive, or negative in this regard, including On the Twin Risk in Autism and Perinatal risk factors for infantile autism

    It looks like our data is kind of a mismatch on this. At least you can get a sense of familiarity with that.

    – pD

  3. Roger Kulp October 4, 2010 at 20:04 #

    De novo mutations can mean any number of things.I have often wondered if there isn’t a “genetic epidemic” of autism,in the last 20-25 years.Something that is causing genetic mutations in fetuses,on the order of thalidomide or even greater.A drug,or food additive,or a cocktail of same,that wasn’t in widespread use in the late 1980s.Now that science has finally put the vaccine issue to bed,maybe we could look at this.

    I don’t know all that much about genetics,but what does classic Mendelian genetics say about this sort of thing?

    De novo mutations can also mean there are mutations that always existed that nobody thought was important before,or that could not be found in the past because of limits of science and technology.

    Chromosome 22q disorders are well associated with autism.Many patients with these disorders often have de novo mutations.Two affected siblings can have different mutations,both undocumented before.I think we could answer a lot more of these questions,if as many autistics as possible,young and old,had a complete genetic profile done.

  4. Sullivan October 5, 2010 at 20:24 #

    A commenter “Bob” at the Age of Autism had this to say about Prof. Bearman’s study:

    First, his comment that parental age is a significant factor in the increased prevalence of ASD – he needs to *show* that the increase in ASD is seen ONLY in children of older parents and not in children of younger parents. Instead, he appears to just make a naked assertion that ASD has increased at the same time that there has been a demographic shift in average parental age. Moreover, his estimate that parental age accounts for 11 percent of the increase appears to be completely made up. He gives NO explanation whatsoever how he arrives at the figure of 11 percent.

    No explanation whatsoever. Well, except for an 18 page paper, peer reviewed and easily downloaded.

  5. Dedj October 5, 2010 at 21:44 #

    It doesn’t really make sense anyway.

    Unless one defines a cut off for ‘older’ and ‘younger’ then they remain relative terms. Also, if the increase is accumulative with increased age then one would expect to see some difference between the ‘lower younger’ and the ‘upper younger’.

    Bobs’ demands indicate that he doesn’t understand what Bearman is claiming or how such statistics are derived. It ignores that the purported risk will also apply to some degree to the upper bounds of the ‘younger’ group.

  6. Tara March 29, 2012 at 15:49 #

    When I read through this a spectrum of bell curves (like successive rainbows) keeps popping up in my mind. Lets say a portion of the population is more susceptible to a certain de nova mutation, which could be related to Epi genome, the cause of mutation could be any number of things. At one end of the curve people produce few mutations while at the other end of the curve people show a high rate of mutation. Now move the curve through time increasing the amount of the mutation trigger. Rates of autism will begin to increase. Now from the “real” world, as opposed to the bell curve, we see more and more diagnosis of Autism. But who would be the “canary in the coal mine” ? People who have:

    *increasing age
    *susceptible and exposed to the trigger (de nova or autism)
    *and possibly those who need the fertility treatments (I am betting treatments do not cause autism)

    The fertility treatments are what made me think, “Why does a person need treatments?” and “Why is there an increase of treatments overt time or lowering fertility?” Is it possible that the reason a person needs treatments is due to a trigger? Is the trigger related to both the fertility treatments and autism? If I am not mistaken, fertility treatments and autism rates have increased over the same time. While one may not beget the other, they may both be due to the same cause. Who knows. There are only so many ways that autism and fertility treatments can be related.

    Back to my curve, those people who are susceptible to this trigger that caused fertility treatments, produce multiple babies, have a second child shortly after (recovery rate) and are aging may be our canaries. Too many stress-ers.

Trackbacks/Pingbacks

  1. Tweets that mention Autism Blog - Social Demographic Change and Autism: part 2 « Left Brain/Right Brain -- Topsy.com - October 4, 2010

    […] This post was mentioned on Twitter by Liz Ditz, Catherina+ScienceMom. Catherina+ScienceMom said: Social Demographic Change and Autism: part 2 http://t.co/U3Obq0E via @kevleitch […]

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