Messages posted by: RAJ

New study raises questions that background noise produces false positives and spurious results and all fMRI may now face problems of acceptance.
The article was discussed over at SFARI autism and is the most viewed article on the SFARI website since it was posted a month ago.
Sometimes a important point can be driven home more directly with humor as was my intention in the comments on the article at:

http://sfari.org/news-and-opinion/news/2011/movement-during-brain-scans-may-lead-to-spurious-patterns

The ground breaking genetic study featured on the home page raises several important questions. De novo copy number variations are caused by reproductive errors (egg or sperm). What is the cause of de novo mutations? Genetic syndromes which may account for 10-15% of all autism cases and the causes of de novo mutations in the severe genetic syndromes may shed light on the causes of CNV?s reported in the Simons Simplex Collection. An important study was published a few months ago that examined the frequency of sperm mutations in workers at a benzene manufacturing plant in China. The study recruited 30 workers who had worked at the benzene manufacturing plant for more than a year and divided the workers into three groups, a low exposure group, a moderate exposure group and a high exposure group. The study included a control group of 11 unexposed workers from the same town.

Every participant in all four groups was found to have de novo sperm mutations including 1p36 sperm mutations. The frequency of the sperm mutations was lowest in the unexposed group, higher in the low exposed group, higher still in the moderate exposed group and highest in the high exposed group.

The 1p36 deletion syndrome is present in 1 in 5,000 to 10,000 newborns:

http://ghr.nlm.nih.gov/condition/1p36-deletion-syndrome

This is the first study that has demonstrated a direct connection between a specific sperm mutation (1p36), a specific severe genetic syndrome (1p36 deletion syndrome) and a specific environmental pathogen (benzene). Many of the severe genetic syndromes are associated with high rates of co-occurring autism. It is compelling that even in the unexposed control group 1p36 sperm mutations was found. There are a number of autism environmental studies funded by the NIH and Autism Speaks currently underway. The CHARGE group is currently studying environmental factors in autism. The CHARGE study group is examining the impact of environmental factors in the womb and in children, as they should, but they are not studying the role of environmental factors in reproductive health prior to conception.

The CHARGE group published a study a year ago that found that living in close proximity (<309m) to heavily congested freeways in California was associated with increased risk for autism. Since benzene, because of its high octane number, is an important component in the production of refined gasoline and diesel fuels one has to consider the possibility that at least some of these cases might be related to de novo sperm mutations associated with long-lasting exposure to benzene particles and other environmental pathogens.

Many of the genetic syndromes associated with high rates of co-occurring (Williams Syndrome, Prader-Willi Syndrome, 22q11 deletion syndrome) and most genetic and epigenetic cases are caused by de novo mutations as contrasted to being inherited events.

The SFARI Autism group, founded by a philanthropist parent, funds millions of dollars into genetic research. In a year end wrap-up of the most important papers published in 2011 commentaries, including comments by the author Dr. Gerald Fischbach, the science director of SFARI Autism, on the role of de novo sperm mutations in the severe genetic syndromes are discussed. Multiple references to similar studies examining the frequency of de novo sperm mutations in using FISH assays in healthy controls are included and might be of interest.

You can find the discussion at:

http://sfari.org/news-and-opinion/news/the-year-in-review

References
Marchetti F, Eskanazi B, Weldon RH et al (2011). Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect
Doi:10.1289/ehp.1103921. Full text available at:

http://ehp03.niehs.nih.gov/article/info:doi/10.1289/ehp.1103921

Volk HE, Hertz-Picciotto I et al (2010). Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 119(6):
Doi:10.1289/ehp.1002835 full text available at:

http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1002835

Autism Speaks and the SFARI Autism organization have published their top ten autism research papers published in 2011. The most important paper published in 2011 may not have come from autism researchers but the from the field of evolutionary biology. Follow the discussion at the SFARI Organization. In the comment section Dr. Gerald Fishbach, the science director of SFARI Autism, weighs in on the studies from evolutionary biology that may solved three questions that have puzzled autism researchers for many years. First, since accuratly diagnosed autistic people seldom reproduce, why hasn't autism become extinct. Second, why is paternal age associated with increased autism risk. Third where did the heritabilty go.

Follow the discussion here:

http://sfari.org/news-and-opinion/news/the-year-in-review

There is an enormouse difference between the ambiguosly defined 'broad autism phenotype' and a handicapping disorder. About 10% of all general population children present with what has been called severe broad autism phenotype features. Milder broad autism phenotype features penetrate even deeper into the general population. These broad autism phenotype features are not pathological at all, they represent common, normal, human characteristic traits that are part of the extraordinary diversity in the human genome itself.

Michael Rutter has proposed a novel two-hit mechanism that states that the genes underlying broad autism traits are not the same as the genetic and environmental factors involved in the disruption of early brain development and the transition to the handicapping disorder.
This widely expanded definition of what autism is and is not has led to the concept of autism being genetically predetermined.

It is a concept that IAN has embraced and the appaling IAN twin study is the only twin study that has included twins where one twin is diagnosed with autistic disorder and the co-twin is diagnosed with PDD/NOS as being phenotypically concordant for autism. Furthermore, critical data presented a year earlier at a London science conference was completly omitted from the final IAN twin study.

I have discussed the IAN twin study with some of the most famous names in autism research and they are appalled at what IAN has done with their twin study. The IAN twin study added more confusion than clarity with respect to the meaning and interpretation of autism twin study's.

The final report of the California Autism Twin Study (CATS) has been published and created a great deal of buzz and excitement in that they interpret their data as suggesting that prenatal environmental factors may be far more important than has been suggested in previous twin studies in autism.

It therefore may be useful to compare the results in two of the most recent autism twin studies, the CATS twin study (2011) and IAN twin study (2009) to the 1995 British twin study which is the most referenced autism twin study ever published.

http://www.ncbi.nlm.nih.gov/pubmed/7792363

http://archpsyc.ama-assn.org/cgi/content/full/archgenpsychiatry.2011.76

http://archpedi.ama-assn.org/cgi/content/full/163/10/907

The CATS study did state, correctly, that:

"Three studies of twins ascertained from clinical samples with a total of 36 monozygotic pairs (concordance rate of 72%) and 30 dizygotic pairs (concordance rate of 0%) have estimated the heritability of autism, or proportion of liability attributable to genetic factors, at about 90%.7 The dizygotic concordance (0%) is substantially lower than the expected rate based on estimates of sibling recurrence rates"

One has to consider the 15 year gap in publication dates between the British twin study and the CATS and IAN twin studies. The 1995 British twin study was published concomitant with the introduction of DSM-IV (1994) with more broadly defined diagnostic criteria for autism and included the new sub-categories of PDD/NOS and Asperger Syndrome. In twin pairs discordant for autism the 'unaffected' twins in the British twin study usually had a history of childhood language disorders or social impairments persisting into adulthood that would now most likely meet diagnostic criteria for PDD/NOS or Asperger Syndrome and may also explain the lower concordance rates in DZ twin pairs in the British twin study compared to more recent twin studies.

Analyzing the underlying data in these three important twin studies suggest that they are all in broader agreement than disagreement especially with respect to MZ twins.

The 1995 British twin study was published by Dr. Rutter's group at King's College 'Autism as a strongly genetic disorder: evidence from a British twin study'. That study is perhaps the most important and referenced study published since 1995. The 1995 British twin study replicates the CATS study more closely than what was suggested by the CATS study with respect to MZ twin pairs. The British twin study using a narrow autism definition did report a pairwise 60% concordance rate for MZ twins. The study also report that in discordant MZ and DZ twin pairs the 'unaffected' twin usually had a history of childhood developmental disorders or social impairments persisting into adulthood. When discordant twin pairs where the unaffected twin had a developmental problem not meeting strict diagnostic criteria for autism were included as concordant, the concordance rate rose to 92%, not all that dissimilar to what the CATS study reported, an MZ probandwise concordance rate of 58% for narrowly diagnosed twins and the combined group consisting of both narrowly defined (genotype concordance and phenotype concordance) autism and more broadly defined autism (genotype concordance but phenotype discordance) reported a 77% concordance rate for the combined groups.

The IAN twin study published in 2009 did replicate the 1995 British twin study. At the IMFAR conference in London in 2008 the IAN group reported that concordance rates for narrowly diagnosed MZ twin pairs (genotype concordance and phenotype concordance) of 60% in both MM and FF MZ twin pairs, exactly the same 60% MZ concordance rate reported in the British twin study. When MZ twins who were discordant for narrowly diagnosed autism were (genotype concordance and phenotype discordance) included the concordance rate for MZ twins concordance rose to 88% compared to the 1995 British twin study of 92%. The final IAN report did not include the data presented at the 2008 London IMFAR Conference and is the only twin study that did so. ( Rosenberg et al 2009).

All three of these twin studies are in broad agreement with respect to MZ twins, there is a 2:1 ratio between narrowly defined (or diagnosed) MZ twins and more broadly diagnosed MZ twins. Why is that important? Because the same 2:1 ratio of MZ twins by chorion type (monochorionic and dichorionic) (MC=66%,DC=34%) has been reported by the East Flanders Prospective Twin Survey. The EFP twin survey is one of the oldest and largest twin registry in existence and it is the only twin registry that has from the beginning systematically examined and recorded perinatal chorion data.

http://books.google.com/books?id=idip6sIxNwUC&pg=PA42&lpg=PA42&dq=twins+mc+dc+ratio&source=bl&ots=CiklzTwQei&sig=XzcasOXkSu55WqU4CgI3WHz2HzQ&hl=en&ei=IzVVTeafEoqugQfg4czpDA&sa=X&oi=book_result&ct=result&resnum=1&sqi=2&ved=0CBMQ6AEwAA#v=onepage&q=twins%20mc%20dc%20ratio&f=false

The CATS study authors have concluded that ?Future studies that seek to elucidate such factors and their role in enhancing or suppressing genetic susceptibility are likely to enhance our understanding of autism'. The study of MZ twins presents with a unique opportunity to examine the effect of different prenatal environments within MZ twin pairs who share 100% of their genes. Are MZ/MC (single placenta) twins who may share the same prenatal environment more alike than MZ/DC twins (and all DZ twins) who do not share the same prenatal environment (separate placenta). Segregating concordance rates in MZ twin pairs for narrowly diagnosed (genotype concordance and phenotype concordance) and broadly diagnosed (genotype concordance and phenotype discordance) by placentation status in MZ twin pairs present a unique opportunity of elucidating the strength or weakness of the interpretation made by the CATS study authors.

In two years the next revision of the DSM (SMA-5)is scheduled to be introduced. What changes will DSM-5 produce and what effects will those changes have on diagnosis and prevalence rates? The proposed changes to DSM-5 has generated a bitter debate and argument over the direction of where DSM-5 is headed towards.

Dorothy Bishop has an excellent article published in the Guardian last month dealing with evolution of autism definition:
http://www.guardian.co.uk/science/blog/2011/jun/07/how-common-autism-diagnosis

Allen Frances was the editor-in-chief charged with editorial responsibility and guiding the various working groups involved in the publication of DSM-IV in 1994. He is a persistent critic of the methodology and direction of development of DSM-5. He is also the most persistent critic of the consequences that occurred concomitant with the introduction of DSM-IV in 1994 for which he accepts responsibility. Here?s what Frances wrote about his own responsibility for the publication of DSM-IV:

?The DSM IV field trials were meticulously conducted, but completely failed to predict the later false epidemics in attention deficit, bipolar, and autistic disorder?.

http://www.psychologytoday.com/blog/dsm5-in-distress/201011/the-dsm-5-field-trials-part-2-asking-the-wrong-question-will-lead-irrel

Mental disorders in DSM-IV are categorical. The Pervasive Developmental Disorders have five sub-categories, Autistic Disorder, PDD/NOS, Asperger Syndrome, Rhett Syndrome and Childhood Disentgrative Disorder. DSM-5 will be dimensional rather than categorical with a single category Autism Spectrum Disorder with severity ratings. Families whose child may possess intellectual disabilities, especially Rhett Syndrome families, strenously object to this proposal fearing that children with intelectual disabilities and co-ocurring autism will be removed from the Autism Spectrum Disorder category and be placed in a newly revised Intellectual Disability category.
The most obvious problem is that it is impossible to calculate a distinctive boundary between disability and normalcy. Children who are reserved and may be obsessively (who doesn't have an obsessive interest in something) interested in academic achievement, science. music. the humanities and the arts and who have no interest in becoming football players or cheerleaders may be hauled before Child Study team tribunals who will use the newly minted ever ready rubber stamp of ?Autism Spectrum Disorder? and be removed from the general school population and be placed in special education services.

At last weeks 2011 IMFAR autism conference in San Diego the California Autism Twin Study (CATS) group presented its second of two oral presentations on their twin study data to date.

This paper concluded that autism does not appear to be the tail end of a normal distribution of autistic-like traits in the general population, a model promoted by genetic determinists such as John Constantino and Fred Volkmar but is instead a discrete clinical entity.

They also found that severity of autism is not heritable and that severity is likely to be the consequence of shared environmental factors.

http://imfar.confex.com/imfar/2011/webprogram/Paper8068.html

I have discussed this with Sir Michael Rutter and we are in broad agreement with with respect to the three major twin studies, the CATS study, the IAN twin study and the 1995 British twin study, who have all replicated the same results.

The concordance rate for narrowly defined (genotype concordance and phenotype concordance)in identical twins is about 60% in all three studies. About 1/3rd of identical twins demonstrate clinical heterogeneity (genotype concordance and phenotype discordance). That 1/3 of identical twins demonstrated clinical heterogeneity is a huge problem for the genetic determinists and may be related to the fact that about 2/3rds of identical twins share the same prenatal environment (single placenta) while 1/3 of identical twins do not share exactly the same prenatal environmnet (seperate placenta).

This new twin study supports Rutter's hypothesis of a 'two-hit' mechanism operating in autism etiology.

The hypothesis states that the genetic influences underlying the broad auitsm phenotype (autistic-like traits) are not the same as the genetic and environmental factors involved in the disruption of early brain development.

In my view, The two hit mechanism also implies that the seperate genetic influences underlying the broad autism phenotype is a background genetic effect on the neuroanatomical alterations involved in the transition to the handicapping disorder.

The CATS study group is the first who has promised to record chorion data (placentation status) and it will be interesting in their final report if they have been successful in recruiting a large enough enough sample of identical twins with unambigous chorion data and whether dichorion type (seperate prenatal environment) is associated with clinical heterogeneity.

The IAN study using Costantino's SRS questionnaire scoring method found that unaffected siblings in the IAN registry had high SRS test scores and that high SRS scores suggests the presence of subtle autistic-like traits (ALT's)that tend to cluster within unaffected siblings.

http://www.ncbi.nlm.nih.gov/pubmed/20889652

Plomin's group in the UK have been studying the prevalance of ALT's in thousands of general population twins recruited from the Twins Early Developmental Study (TEDS) and have found that ALT's occur frequently throughout the general population and that ' Around 10% of all children showed only social impairment,only communicative difficulties, or only rigid and repetitive interests and behavior, and these problems appear to be at a level of severity comparable to that found in children with diagnosed ASD in our sample'.

A new twin study that included nearly 30,000 twin pairs from Sweden now questions the specific association between ALT's and 'autism'. This study found that ALT's are not specific to autism at all. ALT's are associated with risk for a broad spectrum of mental health problems in children and adults that include ADHD, anxiety, conduct problems, depression and substance abuse.

This new twin study suggests that ALT's may be a background genetic effect not specifically to autism but to a broad spectrum of mental health issues in children and adults.

It is well documented that 'autism' is associated with structural anomolies in the developing brain suggesting that non-specific ALT's are a background genetic effect to the neuroanatomical alterations involved in the transition to the handicapping disorder.

The entire concept of the existence of 'Autism Spectrum Disorders' can be questioned and a more appropriate and a relevant category of 'Neurodevelopmental Spectrum Disorders' would be a more accurate 'labelling' for these mental health problems in children and adults.

The search for 'autism' genes or endophenotypes may be akin to a search for the Holy Grail.

http://www.ncbi.nlm.nih.gov/pubmed/21426604

The Autism and Developmental Disability Monitoring Network has just published the largest population study of cerebral palsy ever attempted. This network was established to monitor autism prevelance rates but also includes all children with any developmental problem that become known to the network. This study reviewed the data of 8 years old in four of the states who paricipate in the network whose records are contained in the network.

They identified 476 8 year olds in the network diagnosed with cerebral palsy. Interestingly 39 (8.2%) of the 8 year olds diagnosed with cerebral palsy had a co-occuring diagnosis of autism (DSM-IV criteria).

It is an important study because previous cerebral palsy studies have all been questioned because of they were clinical studies with small sample sizes rather than population based studies.

http://www.ncbi.nlm.nih.gov/pubmed/21273041

Many parents have been calling on the NIH to conduct studies in vaccinated vs unvaccinated groups to find if there is any autism risk between these two groups.

The first study of this kind has been published. The study examined the outcomes of infants who had been vaccinated with Hepatitus B vaccines in the first month of life compared to an unvaccinated control group.

The study found a three fold increased risk for autism in males who were vaccinated against Hepatitus B compared to Males who were not vaccinated with the Hepatitus B vaccine in the first month of life. The risk was most pronounced in white males.

http://www.ncbi.nlm.nih.gov/pubmed/21058170

This study is going to resurrect the entire vaccine debate and it may have been premature to dismiss vaccines as a myth that has been dispelled.

A new study published in the Journal of Pediatric Surgery performed a long term followup in newborns diagnosed with congenital diaphragmatic hernia (CDH).

Of the 41 survivors followed up for neurodevelopmental problems 7% were diagnosed with autism.

http://www.ncbi.nlm.nih.gov/pubmed/20850617

The most recent publication published by the AGP has generated a high profile in the media 'New Autism Genes Discovered!'.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature09146.html

This paper has not undergone any scrutiny.

This study did not use a representative control group. The supplementary data shows that the SAGE control group (N=1880) was comprised of 31% males and 69% females, the complete opposite of the ASD group 4:1 male female ratio. The study did not control for age (as admitted by the authors) nor by IQ.

http://www.nature.com/nature/journal/vaop/ncurrent/extref/nature09146-s1.pdf

1. SAGE cohort: 1,880 control subjects from the larger SAGE case-control study were made
available. The consented sample included 31% males and 69% of females, with mean age of 39.2
(SD 9.1) and 73% of subjects self-identified as European-American, 26% as African-American
and 1% as other

Males may have a higher rate of risk for germline de novo mutations than females:

http://www.bioone.org/doi/abs/10.1111/j.1558-5646.2007.00250.x?journalCode=evol

In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear gene- and organism-specific.

The authors never explain why in heritable cases the parents are unaffected.

The controls used in this study would be unacceptable if they were used in autopsy studies.

It is time for the AGP to employ meaningful control groups that control for age, IQ and gender, this study did not meet any acceptable standards for meaningful control groups. Until they do this type of study screams out for invoking the old bromide of "correlation does not imply causation."

How do CNV's 'cause' autism? No one knows. One possible explanation has come from AIDS researchers. Aids researchers have identified a single gene (CCL31). Lower Copy number variations substantially increase the risk for infections after exposure to HIV:

http://www.sciencemag.org/cgi/content/abstract/1101160v1

The authors of the Nature study claiming CNV's "cause" autism is as big a stretch as an Aids researchers who would claim that lower CNV's in the CCL31 gene "causes" AIDS. Such an absurd claim would be immediately seized on by an unquestioning media who might come up with a catchy headline 'New AIDS Gene Discovered'.

The new IAN initiative on genetics raises a few questions. Why are blood samples not being taken from parents that may determine whether a gene variant is inherited or de novo?

Will IAN use appropriate control groups controlled for IQ and gender.

The IMFAR abstract book is now available:

http://imfar.confex.com/imfar/2010/webprogram/start.html

The CATS study has released a preliminary result and reported that 59.1% of identical twins were concordant for narrowly defined autism.

Three twin studies which have now reported concordance rates for identical twins using a variety of diagnostic schemes and methodologies (population based or parent volunteer based) and have all reported the same consistent,important and startling results. All three studies have reported a consistent 60% concordance rate in identical twins:

Bailey et al 1995 = 60% (narrow definition)
Autism IAN 60.3% (for same PDD diagnosis)
CATS = 59.1% (narrow Definition)

This is an important and consistent finding since 2/3rds of identical twins share a single placenta (same prenatal environment) and are thus equally vulnerable to the consequences of the same prenatal insult. 1/3rd of identical twins develop in seperate placenta and do not share the exact same prenatal environment.

Has the failure of the research community to report concordance rates of identical twins by placentation status led to false impressions and misleading conclusions with respect to the magnitude of the environmental component in Autism?

The California Autism Twin Study (CATS)has released some of its inital findings. This study will be the largest population based twin study ever attempted. Th study has closed its recruiting phase with 225 pairs of twins recruited from the California Division of Special Services.

Abrahams & Geshwind reported, based on personal correspondance with the prinicpal investigator (Joachim Hallmeyer) that "Unpublished estimates for concordance rates for autistic disorder among dizygotic twins may be as high as 25% (J. Hallmayer, personal communication)".

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756414/?tool=pubmed

The initial finding confirms the IAN twin study which reported a concordance rate for fraternal twins of 30%.

A small British twin study (Bailey et al 1995) published in 1995 is the most referenced article published in the last two decades and forms the basis for the concept of autism as being genetically predermined. The authors state that they had recruited all twins pairs in England and failed to find a single case of concordant fraternal twins.

http://www.ncbi.nlm.nih.gov/pubmed/7792363

The CATS study is the first to record chorion type in the twins. It has been assumed that all identical twins share the same prenatal environment. This is not the case. In fact, 2/3rds of identical twins do share the same prenatal environment (single placenta), however 1/3rd of identical twins do not share the same prenatal environment (seperate placenta).

Segregating concordance rates in identical twins by chorion type will test the genetic theory. If concordance rates in identical twins segregated by chorion type are the same, then genetics play a dominant role in autism etiology. If concordance rates are significantly higher in identical twins who share the same prenatal envirnment (single placenta) compared to identical twins who did not share the same prenatal environment (seperate placenta) then the results will provide the first strong evidence that the prenatal environment is as, or more, important than zygosity.

Connie;

Does IAN have any statistics on sibling recurrance rates in your data base?

It would be interesting to compare the fraternal twin concordance rates of 31% to sibling recurrance rates.

Thanks