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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.

Focus on Environmental Causes of Autism in the New York Times

February 28, 2010 Leave a comment

In the 25 days leading up to Autism Speaks’ fifth anniversary, we summarized significant advances in autism science and updates since these advances occurred.  This is a time for celebration and reflection, as well as focusing on next steps.  On the eve of the fifth anniversary, this opinion piece, written by Nicholas Kristof, appeared in the New York Times and has generated considerable interest.

At Autism Speaks, we are investigating environmental links to autism as well as gene-environment interactions through our various grants and initiatives.  In our environmental portfolio, we are currently supporting grants that examine the effects of environmental agents in animals, in which we look for some of the hallmarks of autism.  Researchers in this area are studying animals with different genetic mutations and environmental exposures to the response of the immune system, the effectiveness of the body’s systems at clearing toxins and in changes in the expression of certain genes that occur as a result of the early environment.  In addition we are also funding an expansion of epidemiology and brain development projects, including the Early Autism Risk Longitudinal Investigation (EARLI) and the Infant Brain Imaging Study (IBIS) to learn about gene-environment interactions that may affect the developing fetus.  In the next weeks, we’ll be posting several pieces about gene-environment interactions to educate our community on these important interactions and inform you of the latest autism research in this area.

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.

International Autism Conference – Philippines – Day 5

February 5, 2010 Leave a comment

Today is Thursday, day 2 of the conference and day 5 of our trip here in the Philippines. The session began with a recap of yesterday, given by one of the developmental pediatricians in attendance. By the way, in a country of almost 100 million people, there are less than 40 developmental pediatricians in all of the Philippines. Most are here at the conference.

It has been amazing to see the dedication and kindness in the parents, professionals and teachers in attendance. Everyone wants to learn from each other so that we can all better help families coping with autism. It’s also been fascinating to see a complete lack of divisiveness in the Filipino autism community. They are united in the common goal of helping families, despite organizational affiliations, personal beliefs or social status. A model for the rest of the world with similar goals.

The morning’s presentations focused on the neurobiology of autism, from genetic findings to brain structures and neuroimmunology. Young Shin Kim from Korea talked about the epidemiology of autism around the world – what we know and what we still need to learn. She began by turning the conference room of 1000 attendees into a classroom on basic epidemiology,explaining the difference between prevalence and incidence – terms that even seasoned epidemiologists can easily confuse. Simply put, prevalence measures the total number of individuals in a population with a given disorder at a single point in time. Incidence, on the other hand, describes the number of new cases in a population over a certain period of time. Dr. Kim emphasized that until we can accurately measure the incidence of autism over time, we will not be able to fully understand if we’ve seen a true rise in prevalence from 20 years ago. The talk concluded with an update of the first ever prevalence study being conducted by Dr. Kim in South Korea, supported by Autism Speaks funding. Based on preliminary findings, it is becoming ever clearer that autism truly knows no cultural or geographic boundaries.

Helen Tager-Flusberg, after delayed flights and an unexpected layover, arrived early this morning, just in time to speak this afternoon on language in autism. Tomorrow, Autism Speaks will be hosting an interactive discussion about our Global Autism Public Health Initiative and we can sense the excitement of the conference goers. Come back tomorrow to hear how it went!

By Michael Rosanoff, MPH, Assistant Director, Public Health and Scientific Review and Dana Marnane, National Director Communications and Marketing, Autism Speaks

What is Causing Autism Prevalence to Increase? – Part 2

January 8, 2010 Leave a comment

This part 2 of a 2 part series is from Michael Rosanoff and Andy Shih, Ph.D. who both work in the Autism Speaks science department. This second post is from Andy Shih. Both guest bloggers bios are below the post.

The release of the latest prevalence data by the CDC last week was important in two ways.  One, of course, is its implication for the role of environmental risk factors in autism. The other is how the finding enhances awareness and supports our call for more money for research.

The same can be said for our international epidemiology efforts. As part of our Global Autism Public Health initiative (GAPH), we have been funding and planning prevalence studies with our international partners and colleagues for the past several years. In South Korea, for instance, we are expecting the publication of the first ever prevalence estimate in early 2010. We also have prevalence studies in various stages of development in Albania, India, Ireland and Mexico.  All these efforts involve members of our International Autism Epidemiology Network.

In addition to the contributions these studies can make to our understanding of autism, they will also help raise awareness and inform policy development in parts of the world where affected individuals and families struggle with severe stigma, and in many instances, little or no support and care.  Another way to look at it is that when you conduct a prevalence study, you are basically asking members of the autism community to stand up and be counted. When that happens, especially if the number is anywhere close to the 1 percent figure we have here in the States, their plight and needs can no longer be ignored.

Author Bios

Andy Shih

Andy Shih, Ph.D. is the Vice President of Scientific Affairs at Autism Speaks, where he oversees the etiology portfolio, which includes research in genetics, environmental sciences, and epidemiology. He was responsible for the formation and development of Autism Speaks sponsored international autism research collaborations, the Autism Genome Project and the Baby Siblings Research Consortium. Andy also leads Autism Speaks’ international scientific development efforts, such as the Global Autism Public Health Initiative (GAPH). Andy joined the National Alliance for Autism Research (NAAR) in 2002.

Prior to joining NAAR, Andy had served as an industry consultant and was a member of the faculty at Yeshiva University and New York University Medical Center. He earned his Ph.D. in cellular and molecular biology from New York University Medical Center.

Andy’s research background includes published studies in gene identification and characterization, virus-cell interaction, and cell-cycle regulation. He was instrumental in the cloning of a family of small GTPases involved in cell-cycle control and nuclear transport, and holds three patents on nucleic acids-based diagnostics and therapeutics. Andy is a resident of Queens, where he lives with his wife, daughter and son.

Michael Rosanoff

Michael Rosanoff, MPH, is a member of Autism Speaks etiology team and manages the organization’s epidemiology and public heath research grants. Since joining the organization in 2007, Michael has been the staff lead in overseeing the International Autism Epidemiology Network (IAEN) and is part of the development team for the Global Autism Public Health Initiative (GAPH). He is also a member of Autism Speaks Grants Division, helping oversee the administration of the organization’s grant-making process for research.

Prior to joining Autism Speaks, Michael conducted independent research at the Gertrude H. Sergievsky Center, a clinical, epidemiological and genetic research center at Columbia University Medical Center focused on developmental disorders of the nervous system. His research background is in genetic and psychiatric epidemiology as well as behavioral neuroscience and neuroimmunology, with publications in the fields of epilepsy and depression. Michael earned his Master of Public Health (MPH) in epidemiology from Columbia University’s Mailman School of Public Health and resides in N.J.

What is Causing Autism Prevalence to Increase? – Part 1

January 6, 2010 Leave a comment

This part 1 of a 2 part series is from Michael Rosanoff and Andy Shih who both work in the Autism Speaks science department. The first post is from Michael Rosanoff. Both guest bloggers bios are below the post.

It’s been just over a week but by now most of us have heard that the new autism statistics are out and no less frightening – 1 percent. So the question on everyone’s mind is what is causing this astounding increase in prevalence? Fortunately, in addition to measuring how prevalent autism is in a population, epidemiology can help piece together the rest of the puzzle by examining what is causing autism to be so prevalent. Part of the approach is to tease out some of the “non-casual” factors contributing to the increase over time such as changes in how autism is diagnosed and increasing awareness. While we can’t yet see the full picture, recent research from the U.S. and around the world is showing us that while these factors are clearly playing a role in the rise in autism prevalence, they cannot account for the dramatic increase alone. Epidemiology research can shed light on some of the genetic and environmental factors driving this rise in prevalence, and once we uncover the causes or risk-factors, we can more effectively develop ways to manage this growing problem.

Currently, Autism Speaks is supporting and advising on a number of large-scale epidemiology studies in the U.S. that look at environmental factors potentially contributing to the rise in autism prevalence. These include the EARLI Study, CHARGE, and the National Children’s Study.  In addition, international epidemiology research has been an area of major focus for Autism Speaks. In 2004, Autism Speaks and the CDC (in fact, the authors of the latest prevalence study) co-developed the International Autism Epidemiology Network to promote collaboration and facilitate research among autism epidemiologists worldwide. Today, the network includes over 100 scientists from more than 30 countries.

International research presents unique opportunities to understand the etiology, or causes, of autism by studying different ethnic groups in countries with different environmental conditions than found in the U.S. alone. Epidemiologists can make comparisons of autism prevalence across nations as a means of generating clues about the involvement of genes or environmental exposures. Additionally, some nations have special resources, such as health registries and surveillance systems that can generate large datasets and make previously impossible studies on autism possible. Autism Speaks is currently supporting the iCARE project which combines data from Norway, Sweden, Denmark, Finland, Israel, and Australia to investigate pre- and peri-natal risk factors for autism.

So what we have now is mounting evidence that autism is a major public health issue and epidemiologists have the tools to investigate why autism is more prevalent now than ever before.  The question remaining is what are we going to do about it?  How are we going to enable the necessary research? Autism Speaks is answering the call through our supported research efforts, but our efforts alone are simply not enough to help the 1 percent of the U.S. and possibly global population affected by autism. We need answers and with more support, research will provide the answers families need.

Author Bios

Andy Shih, Ph.D., Vice President of Scientific Affairs at Autism Speaks

Andy Shih, Ph.D. is the Vice President of Scientific Affairs at Autism Speaks, where he oversees the etiology portfolio, which includes research in genetics, environmental sciences, and epidemiology. He was responsible for the formation and development of Autism Speaks sponsored international autism research collaborations, the Autism Genome Project and the Baby Siblings Research Consortium. Andy also leads Autism Speaks’ international scientific development efforts, such as the Global Autism Public Health Initiative (GAPH). Andy joined the National Alliance for Autism Research (NAAR) in 2002.

Prior to joining NAAR, Andy had served as an industry consultant and was a member of the faculty at Yeshiva University and New York University Medical Center. He earned his Ph.D. in cellular and molecular biology from New York University Medical Center.

Andy’s research background includes published studies in gene identification and characterization, virus-cell interaction, and cell-cycle regulation. He was instrumental in the cloning of a family of small GTPases involved in cell-cycle control and nuclear transport, and holds three patents on nucleic acids-based diagnostics and therapeutics. Andy is a resident of Queens, where he lives with his wife, daughter and son.

Michael Rosanoff, Assistant Director of Public Health Research and Scientific Review

Michael Rosanoff, MPH, is a member of Autism Speaks etiology team and manages the organization’s epidemiology and public heath research grants.  Since joining the organization in 2007, Michael has been the staff lead in overseeing the International Autism Epidemiology Network (IAEN) and is part of the development team for the Global Autism Public Health Initiative (GAPH). He is also a member of Autism Speaks Grants Division, helping oversee the administration of the organization’s grant-making process for research.

Prior to joining Autism Speaks, Michael conducted independent research at the Gertrude H. Sergievsky Center, a clinical, epidemiological and genetic research center at Columbia University Medical Center focused on developmental disorders of the nervous system. His research background is in genetic and psychiatric epidemiology as well as behavioral neuroscience, with publications in the fields of epilepsy and depression. Michael earned his Master of Public Health (M.P.H.) in epidemiology from Columbia University’s Mailman School of Public Health and currently resides in Jersey City, N.J.

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