Two new genetic studies – care required

30 Apr

Its always interesting to read about new quality science and two new genetic oriented studies in Nature give us just that – quality science.

The first of two Nature studies released today found that 65 percent of autistic participants shared a variation between cadherin 10 and cadherin 9, a region of the genome that controls cell-adhesion molecules in the brain. Those molecules help brain cells connect, and autism researchers have long suspected that trouble there may be linked to the disorder.

The second study suggested a link between autism and an excess of genetic material associated with ubiquitin, a protein involved with cell-adhesion molecules and connections between brain cells.

Truly fascinating stuff it looks like and yet I think the time is fast approaching when the need for an ethics debate about this becomes paramount.

I am on record as saying that I do not think science could be (as oppose to should be) curtailed when following research interests. In other words, we couldn’t stop an autism researcher from finding a cause or cure even if we wished to. Politics and research science are a bad mix.

However, that should not ever stop us from debating how to use (if at all) such a thing and the following statement from one of the research members is – to me – a bugle call to start thinking of ways we (the autistic community and the scientific community) can do this and remain on good terms:

If we could remove this variant from the population, just take it away … as much as 25 percent of autism would disappear, which is highly significant,” Hakonarson said.

It is indeed, highly significant. It opens up not only a world of scientific possibility bit it must also open up a genuine debate about the ethical issues surrounding this. But before we do this we need to clarify statements like this. 25% of the entire ASD population? 25% of an individual? 25% of the more disabling aspects of autism? 25% of what exactly?

So we need to clarify things like this. Lets hope we can do this very soon and start a respectful debate between two camps who have worked well together up till now – science and neurodiversity.

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38 Responses to “Two new genetic studies – care required”

  1. me.yahoo.com/a/zGh6JKN0u_1w9FkGVM9g1h2nJmpI April 30, 2009 at 14:33 #

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    proceed with caution is right

    There are some major discrepancies in how this is being reported. From an updated AP article:


    One of the studies released Tuesday found that 65 percent of autistic participants shared a genetic variation between cadherin 10 and cadherin 9, a region of the genome that controls cell-adhesion molecules in the brain. The figure for study participants without autism was 60 percent, a statistically significant difference.

    “If we could remove this variant from the population, just take it away … as much as 15 percent of autism would disappear, which is highly significant,” Hakonarson said.

    Big difference between 15% and 25%, but more importantly, I’m not sure how they could see progress in a variant that also exists in 60% of the population. Hopefully this isn’t the gene for walking upright.
    -john

  2. lisanavi April 30, 2009 at 15:07 #

    I agree. 25% of what? And seriously. We’ve known the gene for Huntington’s for years. Down Syndrome, too. There isn’t a magic cure for either of those. There have been genes identified that are believed to cause ADHD? magic cure? no. Just medications that treat the symptoms (I’ve opted for Straterra for my daughter – doesn’t seem to have as much of an affect as an amphetamine would – I like that, I also like that it isn’t a controlled substance)

    I thought that gene studies could also be used to understand the disease more so maybe it would be possible to develop medications to help the more disabling aspects of the disease, but then we don’t have medicine for Huntington’s or down syndrome either. We have medications that treat the symptoms.

    If he means ‘eliminate’ by abortion, well, that’s just scary.
    Especially with something like autism, where the individual is not guaranteed to have profoundly disabling symptoms.

  3. Joseph April 30, 2009 at 16:36 #

    I’m also confused. If the variants exist in 65% of autistics and 50% of the general population, how exactly do you prevent it, without preventing much of the general population?

    The research is interesting in terms of understanding group differences between autistics and non-autistics, but it doesn’t sound like it can tell us anything medical, or how to (euphemistically) “prevent” autism.

  4. brian April 30, 2009 at 17:42 #

    “I’m also confused. If the variants exist in 65% of autistics and 50% of the general population, how exactly do you prevent it, without preventing much of the general population?”

    I think Hakonarson was trying to emphasize that this allele is common in the population (not that individuals with the allele could be eliminated!), in marked contrast to the many less-common alleles with small individual effects that have been identified in earlier linkage and association studies.

    http://sfari.org/news/genome-wide-study-fingers-first-common-risk-factors-for-autism

    Another genetic study of autism out this week implicated some other genes, including DOCK4 (involved in dendritic branching) and a gene that seems analogous to a yeast gene involved in protein processing in mitochondria.

    http://www.ncbi.nlm.nih.gov/pubmed/19401682?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

  5. daedalus2u April 30, 2009 at 20:30 #

    I am not sure I am calculating this correctly, but if 60% of normal controls have the gene and 65% of people with ASDs have the gene, then in order to prevent a single child with an ASD from being born, you would have to abort 387 fetuses who would not develop an ASD.

    ( 149/150 * 0.6 ) / ( 1/150 * 0.65 ) = 0.596 / 0.004333 = 387

    The number of non-ASDs born with the gene divided by the number of ASDs born with the gene.

    On the other hand, if you are a prospective parent who thinks these odds are worth it to avoid having a child with an ASD, you should definitely practice this type of eugenics for yourself.

  6. kyngdingxx April 30, 2009 at 23:09 #

    I wish they would elaborate on this better. “shared a genetic variation between cadherin 10 and cadherin 9,” I don’t know which gene or variant they’re referring to here. I think this gene variant just increases susceptibility, that needs a combination or combinations of variants in other genes to lead to autism, considering 60% of non-autistics have the same variant compared to 65% of those with autism. I wonder where they get the 25% figure from.

  7. Kev April 30, 2009 at 23:09 #

    Note: The Trib story has now adjusted the 25% to 15%.

  8. rajensen088 May 1, 2009 at 04:22 #

    Kev;

    The first error is describing this paper as ‘quality’ science. In the US the author has been making the rounds of the national TV networks proclaiming that 2/3 of autistic children have this genetic variant.

    http://www.cbsnews.com/video/watch/?id=4975818n

    Not once in all his network appearances did he state that the same genetic variant is also found in 60% of the entire population.

    Relatives all over the US are calling parents asking them if they heard about the great genetic breakthrough.

    The 60% of the population who carry this genetic varient are 1.2 times greater at risk for autism than the 40% of the population who do not have the defect.

    Since the male:female ratio in autism ranges from 4:1 (Autistic Disorder) to 9:1 (Asperger Syndrome one can make the argument that there is a genetic variant found in 50% of the total poplution that carries between a 4 to 9 times greater risk (far greater than the 1.2)for autism than in the 50% of the population who do not have the same genetic variant.

    This common genetic variant is carrying an XY sex chromosome. The 50% of population who do not possess this defect instead carry an XX sex chromosome variant.

    Still want to call this study ‘quality’ science, Kev?

    • Kev May 1, 2009 at 20:06 #

      @rajensen088 Yeah 🙂 I’m going to assume you’ve not read the paper? Because you’ve definitely not commented on it.

  9. passionlessDrone May 1, 2009 at 13:27 #

    Hi Daedulus2u –

    On the other hand, if you are a prospective parent who thinks these odds are worth it to avoid having a child with an ASD, you should definitely practice this type of eugenics for yourself.

    Hehe.

    – pD

  10. Joseph May 1, 2009 at 15:48 #

    Is the 15% calculated by subtracting 50% from 65%? If so, that makes no sense to me.

  11. me.yahoo.com/a/TuRz.joYnfzpKUWMPSYwTtN6HTLFunmLzPblUMkn May 1, 2009 at 16:17 #

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    It is interesting that the cadherin and ubiquitin abnormalities which are related to the abnormal genes affect dendritic spine morphology and are also influential on the immune system`s regulatory T-cells. This further suggests the importance of the interplay between genetic predisposition, abnormal immunogenic response and dendritic spine abnormalities in autism.

  12. Matt May 1, 2009 at 17:26 #

    I read the cadherin study last night. There is no discussion within the text of the document of eliminating 15% of autism cases or anything like that. It is a pretty typical conservative paper.

    Seeing the reference to ubiquitin triggered a memory. I went back and looked: the gene whose disruption causes Angelman syndrome, UBE3A, encodes a ubiquitin ligase (E3) enzyme termed E6-AP. Angelman syndrome is frequently associated with autistic-like behaviors, though not classic symptoms.

  13. passionlessDrone May 1, 2009 at 17:38 #

    Hi Dr. Treg –

    It is interesting that the cadherin and ubiquitin abnormalities which are related to the abnormal genes affect dendritic spine morphology and are also influential on the immune system`s regulatory T-cells.

    Indeed! Though I should have thought of it, it also speaks towards a potential mechanism of action for gastro or blood brain barrier permiability problems. If you try to google cadherin and ‘T-cell’, before you get to ‘-cell’, google suggests, ‘tight junctions’ for you. Very nice.

    @Joseph: We are in complete agreement!

    @Kev: Isn’t there some way to modify the template so that only the first 16 characters or so of a user name display, so even if folks can’t configure their profile, your backdoor solution keeps things relatively clean?

    – pD

    • Kev May 1, 2009 at 20:04 #

      Trying 🙂 – its the trackbacks and pingbacks which do the damage to be honest.

  14. cpu52362 May 1, 2009 at 18:38 #

    Off topic but breaking:

    http://cbs4.com/local/Hyperbaric.Chamber.Explosion.2.999108.html

    Link almost gives away the story.

  15. me.yahoo.com/a/TuRz.joYnfzpKUWMPSYwTtN6HTLFunmLzPblUMkn May 1, 2009 at 18:57 #

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    Angelmans also is associated with abnormal dendritic spine morphology
    “Furthermore, we show that cerebellar Purkinje cell number and dendritic branching are not affected in Ube3a maternal-deficient mice, but that dendritic spine development, including spine morphology, number and length, is affected on cerebellar Purkinje cells and on pyramidal neurons in the hippocampus and cortex. Collectively, these data suggest that the neurological deficits observed in AS patients and in AS mice may result from specific abnormalities in synaptic development and/or plasticity.
    http://www.ncbi.nlm.nih.gov/pubmed/17940072

  16. rajensen088 May 2, 2009 at 18:13 #

    Matt;
    You wrote:

    I read the cadherin study last night. There is no discussion within the text of the document of eliminating 15% of autism cases or anything like that. It is a pretty typical conservative paper.

    The lead invesitagor has made that statement in an interview in the Chicago Tribune:

    http://www.chicagotribune.com/health/chi-autism-genetics-29apr29,0,6754959.story

    “If we could remove this variant from the population, just take it away … as much as 15 percent of autism would disappear, which is highly significant,” Hakonarson said.

    Hakonarson has also appeared on the US nationl evening news programs claiming that 2/3 of autistic children possess this mutation never stating that the common variant is found in 60% of the entire population.

    His public statements are unethical and is a misinterpretation of what the article actually states.

    Now if we could completly remove people with an XY pair of sex chromomes (males) a genetic mutation found in 50% of the general public, 100% of autism can simply disappear.

  17. passionlessDrone May 3, 2009 at 00:37 #

    Hello friends –

    I’ve a few questions about this study I’m hoping someone can give me some insight on.

    It didn’t seem like they found all that high an odds ratio, considering the scanned the entire genome.

    Four single nucleotide polymorphisms were identified at position 5p14.1 on chromosome 5 related to autism disorders, with odds ratios ranging from 1.15 to 1.19 and P values of less than 0.000001.

    from : http://www.medpagetoday.com/Neurology/Autism/13960

    So, this leads me to a couple of questions:

    1) If they scanned the entire genome, aren’t your odds of finding something with an odds ratio of 1.19 pretty good; real association or not? For example, Orac blasted the Wakefield monkey study for something similar (I think); making 382838238 tests of genes, finding some that were overexpressed, and clamining that it was the result of vaccination, as opposed to randomness and big numbers. I’m open to the possibility that I’m misreading the press release; and there is something in particular about this study that allows us to ignore this type of problem. Maybe the fact that when multiple large datasets were scanned, the relationship stuck around is significant here?

    2) I’ve seen many, many other genetic studies that claimed to have found higher odds ratios; but in these cases, the authors took the opposite approach of this paper, they found metabolic or other markers, and looked for alleles in specific areas.

    Considering this:

    a) If these authors scanned the entire genome, and didn’t find anything of higher odds ratio than 1.18, does this mean these other studies were random findings? My presumption is that it would seem that if these other polymorphisms showed up in both datasets, something giving a much higher risk of autism would have made an honorable mention or something.

    b) Even if we aren’t worried about the problems with many tests and random associations, does it bother anyone other than me that these odds ratios seem pretty low?

    Maybe my idea of a ‘full genome scan’ is different than what it actually is. (?)

    Any insight is appreciated.

    – pD

  18. rajensen088 May 3, 2009 at 02:06 #

    PD wote:
    a) If these authors scanned the entire genome, and didn’t find anything of higher odds ratio than 1.18, does this mean these other studies were random findings? My presumption is that it would seem that if these other polymorphisms showed up in both datasets, something giving a much higher risk of autism would have made an honorable mention or something.

    Maybe my idea of a ‘full genome scan’ is different than what it actually is. (?)

    Any insight is appreciated”.
    —————————————————–
    The genome wide scans used in these studies is horse and buggy technology compared to the space age technology used in a study published last year:

    http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050254

    This study was the most detailed study of a single healthy middle aged male. The study cost several million dollars and took more than two years to complete. What they reported was astounding, thousands of genetic variances in thousands of genes. :

    “Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel) included 3,213,401 single nucleotide polymorphisms (SNPs), 53,823 block substitutions (2–206 bp), 292,102 heterozygous insertion/deletion events (indels)(1–571 bp), 559,473 homozygous indels (1–82,711 bp), 90 inversions, as well as numerous segmental duplications and copy number variation regions”.

    Had the authors of the studies published last week used that technoogy on the over 11,000 autistic patients, the cost would have been prohibitive, a range of billions of dollars.

    Interestingly, remember a few months ago when another autism ‘hotspot’ was announced in regions near 16P11.2. The headlines were the same ‘New autism gene discovered!’ The authors made the astonishing claim that they has discovered the cause of autism in about 1% of cases.

    http://www.ncbi.nlm.nih.gov/pubmed/18184952?

    Here’s what the new studies found in looking at 16P11.2:

    “We observed a similar frequency of deletions and duplications of the 16p11.2 locus in the ASD cases (~0.3%) as previously reported; however the CNV frequency in the control subjects at this locus was also comparable to that of the cases”.

  19. brian May 3, 2009 at 08:47 #

    Here’s some useful background on genome-wide association studies:

    http://content.nejm.org/cgi/reprint/360/17/1759.pdf

    Note that the authors briefly refer to Parkinson’s disease regarding the association of common haplotypes as susceptibility factors in addition to rarer, larger-effect alleles. Note, too, Parkinson’s, which is likely less heterogenous than ASD, already is associated with about at least half a dozen genes: point mutations and copy number variants in one gene cause a rare dominant form; mutations in a second gene cause a different autosomal dominant form; loss-of-function mutations in four other genes cause autosomal recessive disease; in addition, relatively common “susceptibility variants” that contribute to Parkinson’s disease have been identified in several genes.

  20. Kitty Jones May 24, 2009 at 22:42 #

    There is a treatment for ADHD that we have had great success with and wanted to pass it on. It’s even covered by most insurance. Hope this info helps!
    Comment from lisanavi There have been genes identified that are believed to cause ADHD? magic cure? no. Just medications that treat the symptoms (I’ve opted for Straterra for my daughter – doesn’t seem to have as much of an affect as an amphetamine would – I like that, I also like that it isn’t a controlled substance)
    Responding to firsthand knowledge of the therapy called Neurofeedback (NFB), also called neurotherapy, neurobiofeedback or EEG biofeedback (EEGBF) is a therapy technique that presents the user with realtime feedback on brainwave activity, as measured by sensors on the scalp, typically in the form of a video display, sound or vibration. The aim is to provide real-time information to the Central Nervous System (CNS) as to its current activity. Some approaches believe that conscious understanding and mediation of that information is important for the training process; however, this claim has never actually been verified. Those approaches also believe that neurofeedback training can be understood as being based on a form of operant and/or classical conditioning. In that frame of reference, when brain activity changes in the direction desired by the trainer directing the training, a positive “reward” feedback is given to the individual, and if the change is in the opposite direct from what was intended, then either different feedback is given or the provision of otherwise attained “positive” feedback is inhibited (or blocked). These ideas can be applied in various combinations depending on the protocol decided upon by the trainer. Rewards/Reinforcements can be as simple as a change in pitch of a tone or as complex as a certain type of movement of a character in a video game. This experience could be called operant conditioning for internal states even though no research has yet demonstrated that clear operant response curves occur under those scenarios.

  21. passionlessDrone May 25, 2009 at 13:58 #

    Hey –

    Did we lose a post from Raj here that included a link to the supplemental materials used in this study; one where it showed a rather ridiculous male to female ratio imbalance between the control group and the autism group?

    Strange. Anyways, here’s the link:

    http://www.nature.com/nature/journal/vaop/ncurrent/extref/nature07953-s1.pdf

    The control group included 2519 children of self-reported Caucasian ancestry (mean age
    was 8.7 years, median=9, SD=5.46 and 52.5% males).

    Matching fail.

    – pD

  22. Sullivan May 25, 2009 at 17:15 #

    pD-

    I can’t find any post by RAJ in the spam or moderation queues. I haven’t been following this discussion closely, so I don’t recall that post at all. He is welcome to repost.

    As to your question–“ridiculous” seems a bit much. Yes, there isn’t gender matching. But, the controls have a good representation of the general population–about 50% with slightly more males.

    I guess they could have randomly selected the males for inclusion to get gender balance.

    BUT–this only raises a question. Have you emailed the authors to see if there is a significant difference between the males and females in the control group? I didn’t find that information in a very quick skim of the link you provided. If the males and females in the control group are very similar, there is no systematic error involved, is there?

  23. passionlessDrone May 25, 2009 at 20:02 #

    Hi Sullivan –

    Weird. The missing post I am referring to was up on this thread (I think), b/c I read about it, couldn’t believe it, but was too tired to comment at the time. Maybe RAJ deleted it or something. Or maybe it’s on another thread here, and I’m confused as to which thread he posted it to. Wouldn’t be the first time. (?)

    In any case, the autism group had a similar proportion as to what you would expect for an autism population, approaching 4/1 boys to girls.

    Among these subjects, 703 were male and 156 were
    female, all of whom met diagnostic criteria for autism based on ADI, and 124 met criteria for other ASDs based on ADOS

    RAJ said it more gracefully than this, but considering that the whole point is that we are searching for heritable alleles, and boys not only tend to have lots more autism than girls, and we have many examples of genetic based conditions that are inherited at different rates between the sexes, this would seem to be a pretty amazing oversight. It would have been about the easiest thing to account for; find more normal boys than girls to use as controls.

    I think an autism group with fifty percent males would still be systemic error; one of the most common findings in autism is a much higher rate in males than females. If they had autism rates at near fifty percent between the sexes we would seem to be studying an irregular sample of people with autism. Although, recently Joseph posted for me some links as to some conditions in which this might be reasonable, scanning the entire genome and looking for hits doesn’t seem to be one of them.

    – pD

  24. Kev May 25, 2009 at 20:04 #

    Are we talking about a missing post or comment guys? Not that I can see either…

  25. Sullivan May 25, 2009 at 22:40 #

    Kev,

    sounds like a comment, not a post.

    pD

    I think an autism group with fifty percent males would still be systemic error; one of the most common findings in autism is a much higher rate in males than females. If they had autism rates at near fifty percent between the sexes we would seem to be studying an irregular sample of people with autism.

    Beyond what you think–one can check by contacting the author. Did you attempt this? If there is no difference in the results of the tests on males and females, there is no systematic error introduced.

    I won’t put a question mark this time as the statement is accurate.

  26. Joseph May 25, 2009 at 23:24 #

    Note, too, Parkinson’s, which is likely less heterogenous than ASD, already is associated with about at least half a dozen genes: point mutations and copy number variants in one gene cause a rare dominant form

    PD is also apparently much less ‘heritable.’ So what gives? I think autism is simply a lot more complex. Here’s an example. Suppose there are 3 genotypes that express as what we call ‘autism.’ Each genotype consists of 5 alleles, as follows:

    Genotype#1: (a1+a2+a3+a4+a5)
    Genotype#2: (a6+a7+a8+a9+a10)
    Genotype#3: (a11+a12+a13+a14+a15)

    Let’s say each of the alleles occur in 50% of the general population. Combined, 5 alleles would occur in only about 3% of the population.

    Now, suppose we wanted to find out how common one of the alleles is in autistics, e.g. a6. We know that 1/3rd of autistics would have to have a6. Of the remaining 2/3rds of autistics, half (the background rate) should have it as well. In total, 66% of autistics should have a6.

    So 50% of the general population would have a6, and 66% of autistics would have it as well.

    Imagine what might happen if there are hundreds or thousands of ways to be autistic. There’s no chance a statistical scan will find much of note. It’s a computer science problem, rather than a statistics problem.

  27. passionlessDrone May 26, 2009 at 02:13 #

    Hi Sullivan –

    If there is no difference in the results of the tests on males and females, there is no systematic error introduced.

    One of the most basic facets of having appropriate control groups is that they match, as closely as possible, the group you are trying to study. The goal is to minimize differences between the groups, otherwise, how can you tell if differences are the result of something you are trying to study, or something else?

    But the problem is, what if being male is part of the problem at a genetic level? How can you tell if differences, or no differences, in the results of the test are random, or real? And lets say there was a difference found? In order to determine if it was real or not, do you recommend another massive geocoding, with a more representative control group to account for this? If that study comes back with different results, does that study get the press this one did?

    Another way of looking at this would be, if autism affected one hundred males for every female, do you think it would a good idea to have a control group at fifty/fifty? Or what about a control group of ninety nine/one? The fact that our known ratio, four to one is much smaller serves only to make your range of making an error proportionally smaller.

    – pD

  28. passionlessDrone May 26, 2009 at 02:28 #

    Hi Joseph –

    We know that 1/3rd of autistics would have to have a6. Of the remaining 2/3rds of autistics, half (the background rate) should have it as well. In total, 66% of autistics should have a6.

    I’m lost on what you are getting to here. Why would 1/3 of autistics “have” to have a6? Or are you saying it has been already found? [sorry]

    Imagine what might happen if there are hundreds or thousands of ways to be autistic. There’s no chance a statistical scan will find much of note. It’s a computer science problem, rather than a statistics problem.

    I suspect you may be right in that there are a great number available genotypes and consequent problems with identifying them.

    But this is what led me to my original question on this thread, we seem to have already identified some genotypes that raise autism risk far more significantly than what was reported in this widely heralded study. In these cases, the authors seemingly took a backwards approach from these studies; targeted gene scans based on clinical findings, i.e., we know this and this are measured abnormally in autism, what happens when we scan for mutations in genes known to have impacts on this area. And indeed, it seems that combinations of alleles may confer much more risk than a single allele.

    For example, Aberrations in folate metabolic pathway and altered susceptibility to autism was published a month ago.

    RESULTS: MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (16.3 vs. 6.5%) with 2.79-fold increased risk for autism [95% confidence interval (CI): 1.58-4.93]. The frequencies of MTRR 66A allele (12.7 vs. 21.0%) and SHMT 1420T allele (27.9 vs. 45.3%) were lower in autistic group compared with nonautistic group with odds ratios 0.55 (95% CI: 0.35-0.86) and 0.44 (95% CI: 0.31-0.62), respectively, indicating reduced risk. MTHFR 1298C-allele frequency was similar in both the groups (53.3 vs. 53.6%) and hence individually not associated with any risk. However, this allele was found to act additively in the presence of MTHFR 677T allele as evidenced by 8.11-fold (95% CI: 2.84-22.92) risk associated with MTHFR 677CT+TT/1298AC+CC genotypes cumulatively.

    The greatest relative risk observed in the Nature paper, if I remember correctly, was more like 1.18. Here we have a different group that reported a nearly eight times greater risk of autism based on targeted evaluations. Funny enough, it was only having a1 and a2 that increased risk; a1 wasn’t differentially transmitted. [Haven’t read the entire paper, so I can’t tell yet if they had realistic male/female ratios.]

    What is going on here?

    – pD

  29. Sullivan May 26, 2009 at 04:14 #

    pD-

    you keep acting as though I don’t understand your point. I do.

    The point I made is very clear. You keep avoiding it.

  30. Sullivan May 26, 2009 at 05:36 #

    pD–

    There are some concepts of study design which are obvious enough that I have been assuming you understood them. I can see now that I was wrong.

    Another way of looking at this would be, if autism affected one hundred males for every female, do you think it would a good idea to have a control group at fifty/fifty? Or what about a control group of ninety nine/one? The fact that our known ratio, four to one is much smaller serves only to make your range of making an error proportionally smaller.

    You are making a basic error. If there is a genetic difference between males and females in locations of interest for either the study or control groups, there is no proper gender ratio. In those cases, the proper comparison would be to break out males and females separately. I.e. compare male controls to male subjects and, likewise, females to females.

    If there is a genetic difference in the regions of interest for the study group only, that is a result and should be reported. I.e. if there were, say, a higher rate of the genetic difference amongst males than females in the study group, that would be a big deal and would be worth its own discussion.

    I don’t have access to the paper right now–if/when I do I’ll check if they discuss that.

  31. rajensen088 May 26, 2009 at 12:01 #

    PD write;
    The greatest relative risk observed in the Nature paper, if I remember correctly, was more like 1.18. Here we have a different group that reported a nearly eight times greater risk of autism based on targeted evaluations. Funny enough, it was only having a1 and a2 that increased risk; a1 wasn’t differentially transmitted. [Haven’t read the entire paper, so I can’t tell yet if they had realistic male/female ratios.]

    What is going on here?

    THe Nature paper did not have realistic male/female ratios. The authors published the supplementary data used in the study:

    http://www.nature.com/nature/journal/vaop/ncurrent/extref/nature07999-s1.pdf

    The AGRE data used in the study:
    Males = 83%
    Females = 17%

    The control group used in the study:
    Males = 52%
    Females= 48%

    The study controlled only for gender (white people of European ethnicity). While they recognize that ethnicity can produce different rates of common genetic variants (ie sickle cell disease), they fail to consider the fact that gender (Type 2 Diabetes) may also produce different rates of common genetic variants.

    The authors did not even segregate their findings by gender.

    A few sceptics in the genetic science community consider genome wide association studies to be ‘fruitless’:

    http://www.nytimes.com/2008/09/16/science/16prof.html?_r=3&oref=slogin&pagewanted=all

  32. rajensen088 May 26, 2009 at 12:53 #

    This study also raises questions about the validity of the contents of the AGRE data set which is available to all genetic researchers. One of the most confounding variables in autism research is the inability of the research community to disentangle mental retardation with and without autistic type features.

    The design criteria for AGRE admittance excluded Fragile X patients from inclusion. By definition, the AGRE data contains a subset of mentally retardated subjects with autistic-type features. The AGRE data set does not contain IQ scores thus cannot differentiate a candidate autism gene from a mental retardation candidate gene.

    Remember last years discovery of a rare genetic variation ’16P’ that the authors claimed represent at least 1% of all autism cases:

    http://content.nejm.org/cgi/content/full/NEJMoa075974

    The authors made the same over exaggerated claims about their discovery that the authors of the 5P14 common genetic variant discovery.

    Several studies published since the discovery have not replicated the Boston Children’s Hospital groups discovery:

    http://www.ncbi.nlm.nih.gov/pubmed/19306953?

    Revisiting the original study, the authors claim that the 16P discovery contained in th AGRE data was replicated in in a second group selected from the Boston Children’s Hospital.

    The Boston Hospital Children’s Group did not replicate the AGRE findings since the Boston Children’s Hospital Group contained chidren selected in the author’s own words as:

    “we observed the identical deletion in 5 of 512 children referred to Children’s Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder”

    Still, the Boston Children’s Hospital is now selling a ‘genetic test for autism’ based on the hyper exaggerated discovery that 16P genetic variations account for ‘at least 1% of all autism cases’.

    How long will it take for authors of the 5P study to offer a prenatal gene test for autism, a common genetic variant found in 60% of the entire population. After all, the lead author of the 5P study has claimed that if we could wipe out the 5P mutation, 15% of all autism would just disappear.

  33. rajensen088 May 26, 2009 at 12:56 #

    Erratum:

    My previous post read:
    The study controlled only for gender (white people of European ethnicity).

    Should have read:
    The study controlled only for ethnicity (white people of European ethnicity).

  34. Joseph May 26, 2009 at 13:35 #

    I’m lost on what you are getting to here. Why would 1/3 of autistics “have” to have a6? Or are you saying it has been already found?

    It was a hypothetical model, if that wasn’t clear. Briefly, if there are many complex genotypes that express as autism, it’s not practical to find single alleles that associate statistically with autism.

    Basically, difficulties in finding straightforward genotype-phenotype associations are not evidence of lack of heritability. They evidence lack of problem solving technology. There are other ways to see if a phenotype is heritable.

  35. Sullivan May 26, 2009 at 16:14 #

    rajensen088 wrote:

    THe Nature paper did not have realistic male/female ratios. The authors published the supplementary data used in the study:

    Which only matters if there is a difference between the males and females in the control group.

    If the goal was to understand the paper either you or passionlessdrone would have contacted the author and posted his answer here.

    I’ll save you the trouble (from the contact author):

    …this locus we reported on 5p14.1 contributes to both male and female autism and it makes no difference if we use males or females as controls (we loose some power if we drop out 50% of the females but the locus remains significant; the replication is also performed in trios where this has not impact but the bottom line is that MAF is the same in both sexes of healthy controls

    They could remove many of the females from their control group. It would change the statistical power but not the conclusion.

  36. Sullivan May 26, 2009 at 16:19 #

    How long will it take for authors of the 5P study to offer a prenatal gene test for autism, a common genetic variant found in 60% of the entire population. After all, the lead author of the 5P study has claimed that if we could wipe out the 5P mutation, 15% of all autism would just disappear.

    Did you lose track of the blog post that started this discussion? That is essentially Kev’s thesis. He even got the quote correct (25% in the quote)

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