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Commentary on the LA Times Series on Autism

January 3, 2012 18 comments

Posted by Autism Speaks scientific advisory board member Irva Hertz-Picciotto, PhD, MPH. As an epidemiologist at the University of California-Davis MIND Institute, Hertz-Picciotto studies exposures to environmental chemicals, their interactions with nutrition and pregnancy and their effects on prenatal and early child development.

Alan Zarembo’s series on autism in the LA Times  covers a great deal of territory and has brought to light a wide range of personal stories that exemplify the complexity of issues surrounding autism diagnosis, treatment choices and effectiveness, impact on families and population incidence. Zarembo should be commended for the substantial work he has done researching inequities in the delivery of services. Of notable concern, he has put a spotlight on what appear to be serious racial and ethnic disparities in the California Department of Developmental Services (DDS) system and the provision of therapies. If his figures are correct, this result should stimulate an analysis of how to right this situation and ensure that appropriate opportunities are made available to all families with affected children.

Zarembo has also highlighted adults living with an autism spectrum disorder (ASD) but diagnosed late in life. We have too long overlooked the struggles faced by adults with autism as they try to find ways to be productive, live independently and connect with others.

My remaining comments pertain to Zarembo’s conclusions about the rise in autism diagnoses and the role of environmental factors. First, he is right that there is substantial variability in rates of diagnoses in different regions, and that we should not confuse diagnoses with the actual incidence of disease. Not all persons who meet criteria have been correctly diagnosed, and the degree to which this is true has likely changed over time.

Nevertheless, impressions are not the same as a scientific analysis. Zarembo has not demonstrated that the rise is purely social and cultural.  My colleague Lora Delwiche and I published the first quantitative analysis of how much of the increase in diagnosed cases in California could be explained by artifacts (changes in diagnostic criteria, earlier age at diagnosis and inclusion of milder cases).1 We used California state data that provided statistics over many years and found that the numbers simply do not add up. In other words, the actual increase has been far larger than these artifacts could have produced. Combining our results with those of another research team, it appears that about half of the increase in diagnoses in California is due to changes in diagnostic criteria or practices.2 These results left about a three-fold increase unexplained as of 2007. And autism diagnoses in California have continued to rise both in areas with low rates and in areas with high rates. Zarembo is interested in explaining the geographic variation, but the explanations for variation spatially are not necessarily the explanations for variation over time.

These statements were particularly misleading:

“No study points to an environmental reason for the worldwide explosion in cases over the last two decades.

Given the slow pace of genetic change in large populations, genes can’t account for the surge either.

That suggests the explanation for the boom lies mainly in social and cultural forces, notably a broader concept of autism and greater vigilance in looking for it.”

The logic that leads from the first two sentences to the third involves huge assumptions.

How many studies have been done of environmental causes? Very few!  And of these, most were extremely poor studies involving very small samples or lacking individual-level data. Is it surprising we’ve uncovered few leads?  The funding for environmental factors has been paltry – somewhere around $40 to $60 million over the last 10 years, while more than $1 billion has been spent on studying autism genetics.  To imply that environmental factors can be dismissed and that only social/cultural factors should be pursued is nonsensical.

It should be noted, however, that if anyone is looking for “one” environmental factor to explain the increase, they will certainly be disappointed. It doesn’t exist. Autism is far too complex. Moreover, to the extent the increase is due to diagnostic differences over time, we need to find explanations both for the increasing numbers of diagnoses and for the autism that has been around “all along.” In fact, data are emerging about quite a number of environmental factors. In 2011, major papers were published supporting contributions from maternal nutrition around the time of conception (here and here), traffic-related air pollution, and season of conception.3-6 Earlier papers indicated associations with pesticides  (here and here) and air pollution.7-9

One concern raised about the increase in diagnoses is a type of ‘inflation’ from inclusion of a growing number of high-functioning persons whose diagnosis is more likely to be Asperger syndrome than classic autism. This may apply to some studies of changes over time, but in our analysis of CHARGE study data, most of the cases were low functioning.10 This would likely be true for the majority of persons with ASD served by the California Department of Developmental Services (DDS), because in order to qualify for state services, they must have “significant functional limitations” in three areas of major life activities. This requirement would exclude most of those who are higher functioning.

With regard to genetics, Zarembo’s article leaves out the most current information: the largest and most statistically robust study of twin pairs found that 38 percent of concordance is due to shared genetics with 58 percent due to shared environmental factors (most likely prenatal and perinatal).11 This result completely overturns the widespread assumption, based on a number of previous small studies, that the causes of autism are overwhelmingly heritable, or genetic. Unfortunately, most analyses of twins make the incorrect assumption that genes and environment do not interact to influence risk for disordered brain development. This interaction is real, and one study has already shown a whole class of genes that primarily affect development in children whose mothers had not taken prenatal vitamin supplements during the months preceding and immediately following conception. 3

In summary, Zarembo’s investigative journalism provides unusual depth into difficult aspects of autism occurrence and the social policies that bear on the lives of affected families. He has raised several critical challenges facing the autism community. What was lacking from his series is a more balanced view of the role environment likely plays and the need to advance the agenda of discovering modifiable causative factors.

Autism Speaks is one of a few organizations that have begun to turn in this direction. I look forward to a continued strong commitment by Autism Speaks and others willing to support and significantly expand the scientific research aimed at identifying and understanding environmental contributions to autism, factors driving increased prevalence and ways to intervene so as to eliminate or lower human exposure levels. This will be the fastest road to reducing the occurrence of ASD in the next generation.

References
1             Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology 2009;20: 84-90.
2             King M, Bearman P. Diagnostic change and the increased prevalence of autism. Int J Epidemiol. 2009; 38:1224-34.
3             Schmidt, R J, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology 2011;22:476-85.
4             Cheslack-Postava K, Liu K, Bearman PS. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics 2011;127:246-53.
5             Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 2011;119: 873-7.
6             Zerbo O, Iosif AM, Delwiche L, Walker C, Hertz-Picciotto I. Month of conception and risk of autism. Epidemiology 2011;22:469-75.
7             Roberts EM, et al. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007;115:1482-9.
8             Eskenazi B, et al. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect 2007;115:792-8.
9             Windham G, Zhang L, Gunier R, Croen L, Grether J. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay Area. Environ Health Perspect. 2006; 114(9):1438-44.
10           Hertz-Picciotto, I. et al. The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ Health Perspect. 2006;114: 1119-25.
11           Hallmayer, J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011(68):1095-102.

Autism Speaks Science Staff Reports on New Parental Age and Autism Risk Study

February 9, 2010 Leave a comment
A new study of parental age and autism risk was published online yesterday in the journal Autism Research.  The study reports on approximately 5 million births in California from 1990-1999 and reaffirmed previous data showing that parents who are older have an increased risk of having a child with autism. The study found that, regardless of the father’s age, mothers over 40 had a 51% increase in risk of having a child with autism compared with younger mothers (aged 25-29). Fathers over 40 had 36% increase in risk compared to younger fathers,  but only when the mother was in the younger range.

These numbers may sound alarming, but lets further discuss what they mean.  The 51% increase in risk for mothers over 40 can also be described as approximately 1.5 times the chances of having a child with autism compared to mothers 25-29.  In other words, the increased chance of having a child with autism was less than two-fold among this group. Thus, mother’s age and father’s age only slightly increased the risk for autism, and should not be viewed as a specific cause of autism. While the exact biological mechanism behind the relationship between delayed parenthood and ASD is unknown and warrants further investigation, it is well understood that pregnancy in older individuals is associated with higher risk for low birth weight, prematurity, and chromosomal abnormalities.  We also know that prematurity is a risk factor for autism spectrum disorders (ASD).  It also is important to keep in mind that the majority of pregnancies in older fathers and mothers are healthy.

Do changes in the ages at which parents are having children explain the dramatic increase in prevalence of ASD?  The study examined births over a decade, a period during which the prevalence of ASD has increased by over 600%.  The authors estimated that advanced maternal age only accounts for 4.6% of the increase in autism cases in California during the study period.  Thus, it is clear that, while changes in the age at which parents are having children may account for some of the increase in prevalence of autism, a large amount of the increase in prevalence remains unexplained.

As with any study, there are many methodological details to be considered.  The strength of this study lies in the large population considered. These findings reinforce other data reporting parental age is a risk factor for autism.  The study population came from the California Department of Developmental Services (DDS), which is estimated to capture about 75-80% of all “true” autism cases.  To be included in the DDS, parents had to actively seek out services.  As such, parents of autism cases in the DDS are likely to have higher levels of education and socioeconomic status, and are perhaps older than what would be found in a population-based sample. We know from this and other research that higher levels of education and sociecomic status are associated with higher rates autism (perhaps because people in this demographic category are more likely to seek diagnostic services), so it is possible that this study may overestimate the effect of parental age on autism risk. Also, it is worth noting that this study considered cases of autistic disorder only, not diagnoses from the rest of the autism spectrum.

To summarize, it is important to remember that as we dig deeper into different contributions to autism risk, we will uncover different pieces of the larger puzzle that may not seem to fit, at least at first.  Some, pieces, like this one regarding parental age, are especially intriguing because they blend biological with the socio-environmental factor of delayed parenthood.   As for biology, it is also true that as people age, modifications occur in the way the genetic code is read. This field of research known as epigenetics and is one part of the larger study of gene x environment interactions.  The topic of gene-environment interaction has been reaching our community with increasing frequency and so Autism Speaks staff and some Guest Scientists will be offering a series of blog posts specifically on these topics.  Please stay tuned. We look forward to putting this puzzle together with you.

To learn more about the recent findings in autism epidemiology, including additional findings on the effects of parental age, please see our list of the Top Ten Science Accomplishments of 2009.

Reference: Shelton JF, Tancredi DJ and Hertz-Picciotto I (2010) Independent and Dependent Contributions of Advanced Maternal and Paternal Ages to Autism Risk. Autism Research.  3: 1-10.

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