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Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity

28 Aug

A recent study from Sweden presents another autism prevalence estimate. Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity is available online free. My analysis is on the Autism Science Foundation blog as Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity

I will point out that the methodology differs from the American prevalence estimates from the CDC. In particular, where the CDC looks at children of a given age (8 years old) in a given year, the Stockholm Youth Cohort study considers a cross section of autistics, ages 4 to 23. The prevalence, especially for autistic disorder, is relatively flat for autistics born in the 1990s, a time when there was supposedly an increase of 100’s of percent in autism prevalence. In other words, the study doesn’t support the idea of an epidemic.


By Matt Carey

How Research into Chronic Fatigue Syndrome Turned into an Ugly Fight

24 Jul

Judy Mikovits is a researcher who, in recent years, has focused on chronic fatigue syndrome. In her work she published a paper potentially linking chronic fatigue syndrome to XMRV (Xenotropic murine leukemia virus-related virus). In her unpublished work, her team discussed the possibility that autism was also linked somehow to XMRV.

There has been much drama involving Judy Mikovits, her research and her former institution (the Whittemore Peterson Institute) over the last year.

The Daily Beast has an interview with Judy Mikovits. The first since the legal issues arose last year. How Research into Chronic Fatigue Syndrome Turned into an Ugly Fight. The interview gives her side of the story in much of the events. One can read them at the Daily Beast, but I’ll focus on this section here as it applies to the science involved:

Meanwhile, other research groups around the country were trying to replicate the 2009 results, but in the two years that followed, almost all had failed. The word “contamination” began to surface more and more frequently.

In the summer of 2011, Mikovits and her young lab assistant, Max Pfost, began poring through their notebooks, trying to find where such a contaminant might have entered their process.

In July, she says, she found it—an entry from March 2009 indicating that a culture of the XMRV virus had been placed into the same ice chest with the rest of the lab’s blood samples. Mikovits says she was out of town the day this occurred.

To this reader, this is a sign that the upcoming multi-center attempt to replicate the XMRV/chronic-fatigue-syndrome work is going to come out negative (like the multiple other XMRV/CFS studies published so far trying to replicate her work). There was contamination in her lab’s process.

This does not speak directly to the XMRV/autism work, but two papers have:

Lack of Infection with XMRV or Other MLV-Related Viruses in Blood, Post-Mortem Brains and Paternal Gametes of Autistic Individuals

PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism.

So, we have an unpublished result supposedly linking autism with XMRV from a laboratory where the principle investigator is telling us there was a contamination issue and two papers saying there is no detectable link?

While I doubt the XMRV/autism story will die out completely, it strikes this observer that it’s time to look elsewhere for answers.

The Wakefield Rehabilitation? Not really.

18 Oct

Reading about Andrew Wakefield gets old and tiring. I’m sure that isn’t news to readers here. Writing about Andew Wakefield gets very tiring. Who wants to keep reminding him/her self about a man who has caused so much harm to both the autism communities and public health in general? Who wants to read about dishonesty and unethical behavior?

I can only imagine that Brian Deer must want to put his award on a shelf and move on.

Which all begs the question: why do I think people reading Left Brain/Right Brain might want to read about him again? Because in this case it isn’t about Mr. Wakefield. Rather it is about his supporters. People who put aside the proved charges of dishonesty and unethical behavior. People such as Kent Heckenlively of the Age of Autism blog who are looking for The Wakefield Rehabilitation. It’s about how and why authors cite previous literature, and not reading too much into citations.

Beyond the hopes of those supporting Andrew Wakefield, there is some good research here and a bit of information about how and why people cite certain papers in the scientific literature.

First, how is Mr. Wakefield being “rehabilitated”? Answer: his papers were recently cited in a recent study. Seriously, something that small. That’s how hard people have to look for validation for Mr. Wakefield. A few citations and he’s on the road to rehabilitation.

The new paper isn’t by just any team, though. The study, recently out in PLoS One is Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances. The study is a follow-on to the PLoS One paper by Hornig et al., Lack of association between measles virus vaccine and autism with enteropathy: a case-control study.

Why is that important? “Lack of association…” is the paper which definitively put an end to the Wakefield MMR hypothesis. The team tried, with meticulous attention to detail, to replicate the most important factors of various Wakefield MMR-autism papers. They studied children with autism and gastro-intestinal complaints. They restricted their study to children who had demonstrated clear need for endoscopy (one major difference from the Wakefield studies). They were very careful about correctly reporting the patient histories (another major difference). They tested intestinal biopsy samples for measles virus (similar to as study by the Wakefield team), but were very careful to avoid contamination (unlike the Wakefield studies). The recent study used multiple laboratories to test for measles virus (Wakefield used two: his own and the O’Leary laboratory). Unlike Mr. Wakefield, the recent study reported on results from all the laboratories (Mr. Wakefield neglected to mention the results from his own laboratory which were contradictory to his theory).

Hornig et al. wrote:

The work reported here eliminates the remaining support for the hypothesis that ASD with GI complaints is related to MMR exposure. We found no relationship between the timing of MMR and the onset of either GI complaints or autism. We also could not confirm previous work linking the presence of MV RNA in GI tract to ASD with GI complaints.

About as clear a conclusion as I’ve ever seen. “The work reported here eliminates the remaining support for the hypothesis that ASD with GI complaints is related to MMR exposure.”

So, what about the new paper and the citations? Well, members of the team that produced the Hornig et al. study did further research on the tissue samples taken. Brent L. Williams heads up the author list on the new study.

Here is the (highly technical) abstract from the new study by Williams et al.:

Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.

If this were really about the autistics and not about Andrew Wakefield, those claiming that there is something different about the GI disturbances in autistics should be extatic. Here is a top notch team pointing to a possible real difference. In the kids tested, the genes were expressing enzymes and transporters–i.e. the genes are performing differently–for autistic kids. Also, they are seeing differences in the bacteria in the autistic kids.

Not only that, but these kids benefited from dietary intervention, although it isn’t specific to the autistic kids: “Beneficial effects of dietary intervention on GI disturbances were reported for all AUT-GI and Control-GI subjects with FA.”

But, it apparently isn’t about the autistics or the research when it comes to the Age of Autism. It’s about rehabilitating Andrew Wakefield’s reputation. (With apologies in advance–the image that comes to mind is a team that has been performing CPR on his reputation for years now. It’s time to move on.)

The important piece of this study, according to Mr. Heckenlively, is that they cite some of Andrew Wakefield’s papers. In particular:

Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, et al. (2000) Enterocolitis in children with developmental disorders. Am J Gastroenterol 95: 2285–2295.

Wakefield AJ, Ashwood P, Limb K, Anthony A (2005) The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder. Eur J Gastroenterol Hepatol 17: 827–836

Ashwood P, Anthony A, Torrente F, Wakefield AJ (2004) Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol 24: 664–673.

Mr. Heckenlively appears to have built a nice straw man argument in which every thing Mr. Wakefield has done is now discredited. Somehow citing a paper by Mr. Wakefield then becomes some sort of a statement that everything he did was actually right. Both sides of that argument are false. The authors should cite what is in the literature. By citing, say, the Ashwood (2004) paper, they aren’t saying that, say, the 1998 Wakefield Lancet paper is now “rehabilitated’.

Notice that the authors didn’t cite the 1998 Lancet paper. One big reason: it’s been retracted. Which begs the question, why are the authors citing Wakefield et al. (2000)? The paper in the American Journal of Gastroenterology has also been been retracted:

On 28 January 2010, the UK General Medical Council’s Fitness to Practice Panel raised concerns about a paper published in the Lancet by Dr Wakefi eld et al. (1). The main issues were that the patient sample collected was likely to be biased and that the statement in the paper, that the study had local ethics committee approval, was false. Th ere was also the possibility of a serious conflict of interest in the interpretation of the data. Th e Lancet has now retracted this paper (1). Th is paper in the American Journal of Gastroenterology (AJG) (2) also includes the 12 patients in the original Lancet article and therefore we retract this AJG paper from the public record.

One really shouldn’t cite things that have been retracted from the public record. So, is there some message that Williams et al. are trying to send us? Are they saying that Andrew Wakefield was correct all along? Hardly. That paper was retracted in May of 2011, the same time that Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances was submitted to PLoS One. The authors weren’t aware of the retraction. Says a lot about how closely they follow Andrew Wakefield, don’t it?

Apparently, the authors have contacted PLoS about the citation, and it will be corrected to notify readers of the retraction. That is the right thing to do. It isn’t a statement about Mr. Wakefield’s research, other than this paper was retracted.

Authors can’t control the message bloggers may try to create from their research (heck, one of the authors, Ian Lipkin, consulted on the recent movie “Contagion”, a main character is a blogger whose message is unscientific and irresponsible). From what I’ve heard, the authors are still very clear on the message of their first PLoS paper: “The work reported here eliminates the remaining support for the hypothesis that ASD with GI complaints is related to MMR exposure. ”

I think the point was made pretty clearly. Mr. Heckenlively in his excitement read way too much into this new paper. Not surprisingly, he just goes on and on making more mistakes. Consider this paragraph:

Isn’t Dr. Wakefield supposed to be some super-villain, leading all of us gullible parents to believe that vaccines aren’t quite as safe as sugar water? Didn’t he make up fake diseases? So, after being stripped of his license to practice medicine in the U. K., it turns out there really is something called autistic entercolitis and ileo-colonic lymphoid nodular hyperplasia in children with autism. At least Dr. W. Ian Lipkin seems to think so.

Wow. All this is extrapolated from a single sentence in the introduction of the paper: “Macroscopic and histological observations in ASD include findings of ileo-colonic lymphoid nodular hyperplasia, enterocolitis, gastritis, and esophagitis [2], [3], [4], [5], [6], [7].”

What does that sentence mean? Simple interpretation: others have reported these findings. Not “we confirm that these findings are real”. Given that reference [3] (a retracted Wakefield paper) may be removed or noted to be retracted, the only support for “enterocolitis” will be gone from the paper.

Mr. Heckenlively wrote “Although this study used a relatively small sample of gut biopsies from children with autism (Hey, isn’t that what Wakefield got in trouble for? Or is my memory failing me?),”

Mr. Heckenlively, your memory is failing you. The findings of the General Medical Council are easily found online.

Let me remind you of some of that document:

The Panel concluded that Dr Wakefield’s shortcomings and the aggravating factors in this case including in broad terms the wide-ranging transgressions relating to every aspect of his research; his disregard for the clinical interests of vulnerable patients; his failure to heed the warnings he received in relation to the potential conflicts of interest associated with his Legal Aid Board funding; his failure to disclose the patent; his dishonesty and the compounding of that dishonesty in relation to the drafting of the Lancet paper; and his subsequent representations about it, all played out against a background of research involving such major public health implications, could not be addressed by any conditions on his registration. In addition, the Panel considered that his actions relating to the taking of blood at the party exemplifies a fundamental failure in the ethical standards expected of a medical practitioner. It concluded that conditional registration would not mark the seriousness of such fundamental failings in his duty as a doctor

and

The Panel made findings of transgressions in many aspects of Dr Wakefield’s research. It made findings of dishonesty in regard to his writing of a scientific paper that had major implications for public health, and with regard to his subsequent representations to a scientific body and to colleagues. He was dishonest in respect of the LAB funds secured for research as well as being misleading. Furthermore he was in breach of his duty to manage finances as well as to account for funds that he did not need to the donor of those funds. In causing blood samples to be taken from children at a birthday party, he callously disregarded the pain and distress young children might suffer and behaved in a way which brought the profession into disrepute.

Mr. Heckelively also poses the question: “Didn’t he [Andrew Wakefield] make up fake diseases?”

That would be “autistic enterocolitis”, a term Andrew Wakefield coined and a condition which still, 13 years later, doesn’t have support. Autistic enterocolitis is not just any and all GI disturbances in autistics. Enterocolitis is “…an inflammation of the colon and small intestine”. Note the “and”, there. Even more important, the PLoSOne paper is not about inflammation at all.

Mr. Heckenlively finishes with the rather hopeful, wishful thinking statement: “But if a big shot scientist like Dr. W. Ian Lipkin is quoting Dr. Andrew Wakefield as a reliable source, maybe the rest of the world will soon be doing the same thing.”

Again, wow. Here we have Ian Lipkin, one of the team that just put an end to the Wakefield-MMR hypothesis. Again, let’s remind ourselves, Ian Lipkin is part of the team which wrote: “The work reported here eliminates the remaining support for the hypothesis that ASD with GI complaints is related to MMR exposure.” There is such a major disconnect between that statement (which, yes, Dr. Lipkin stands by) and what Mr. Heckenlively wrote that I am just left in amazement.

This isn’t a story about rehabilitation. This is a story about diversion. Diversion of attention away from important subjects in autism. These include the medical treatment of major health problems. How does one treat something like bowel problems in individuals with communication and/or sensory difficulties? That’s a big question that gets lost in this whole “Andrew Wakefield” discussion. Research like this new paper is important in that respect: is there something specific to kids with autism, regression and GI disease? Leave aside any discussion about GI being linked to the regression, how do you treat it? I, for one, am glad to see something come out of this research project than just the “MMR doesn’t cause autism and GI disease” conclusion. Instead of trying to read the tea leaves of this paper and try to recoup the damage Andrew Wakefield did to his reputation, why don’t we just read the paper in the context of what this might tell us about the health problems of autistics?

Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?

16 Sep

Metabolic disorders became a major point of discussion within the autism community a few years back. The upside was that a potentially important area of research (and not just within autism) was highlighted. The downside was that a lot of misinformation was propagated.

A lot of answers are still unknown precisely. The prevalence of metabolic disorders in autism, specifically mitochondrial disorders, was likely exaggerated by many, but that doesn’t make it an unimportant question. The question of how metabolic disorders fit into the etiology of autism is another open and valuable question.

The current study addresses the question of whether autistics should be routinely screened for metabolic disorders. On some very real level, I’m sure many people think that people should be screened for everything. If screening were fast, accurate, cheap and non-invasive, this would be a good point. But, this isn’t really the case. So the authors pose the question: Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?

The paper comes from a group at APHP, Reference Center for Inherited Metabolic Disease, Hôpital Robert Debré, Paris, France.

Here is the abstract:

BACKGROUND:

In the investigation of autism spectrum disorders (ASD), a genetic cause is found in approximately 10-20%. Among these cases, the prevalence of the rare inherited metabolic disorders (IMD) is unknown and poorly evaluated. An IMD responsible for ASD is usually identified by the associated clinical phenotype such as dysmorphic features, ataxia, microcephaly, epilepsy, and severe intellectual disability (ID). In rare cases, however, ASD may be considered as nonsyndromic at the onset of a related IMD.
OBJECTIVES:

To evaluate the utility of routine metabolic investigations in nonsyndromic ASD.
PATIENTS AND METHODS:

We retrospectively analyzed the results of a metabolic workup (urinary mucopolysaccharides, urinary purines and pyrimidines, urinary creatine and guanidinoacetate, urinary organic acids, plasma and urinary amino acids) routinely performed in 274 nonsyndromic ASD children.
RESULTS:

The metabolic parameters were in the normal range for all but 2 patients: one with unspecific creatine urinary excretion and the other with persistent 3-methylglutaconic aciduria.

CONCLUSIONS:

These data provide the largest ever reported cohort of ASD patients for whom a systematic metabolic workup has been performed; they suggest that such a routine metabolic screening does not contribute to the causative diagnosis of nonsyndromic ASD. They also emphasize that the prevalence of screened IMD in nonsyndromic ASD is probably not higher than in the general population (<0.5%). A careful clinical evaluation is probably more reasonable and of better medical practice than a costly systematic workup.

They conclude that the prevalence of inherited metabolic disorders (IMD) in non-syndromic (i.e. those where an underlying condition is considered to be the cause of autism) autistics is about the same as for the general population (<0.5%) and that routine screening does not give insight into the cause of autism.

Here are a couple of paragraphs from the study:

Notably, a recent study pointed out that mitochondrial dysfunction may be involved in ASD [30]. In this report, plasma lactate determination was performed in a restricted sample of 69 patients with ASD. Twenty per cent of them displayed hyperlactatemia and 7% fulfilled the criteria for a disorder of oxidative phosphorylation (OXPHOS) [30]. This initial study has limitations as the autistic clinical phenotype was not well defined. More recently, a retrospective study of 25 patients with a primary diagnosis of nonsyndromic autism who were further determined to have enzyme- or mutation- defined OXPHOS deficiency showed that 96% of these patients actually exhibited clinical symptoms differentiating them from idiopathic autism [31]. These results suggest that careful clinical and biochemical reappraisal is warranted in patients with ASD initially considered as nonsyndromic, but also confirm that ASD patients with OXPHOS dysfunction often exhibit other symptoms such as microcephaly, marked motor delay, sensorineural deafness, oculomotor abnormalities, exercise intolerance, cardiomyopathy or renal tubular dysfunction. Accordingly, we decided not to screen for hyperlactatemia in our nonsyndromic ASD population. Furthermore, normal plasma lactic acid concentrations do not exclude the presence of a mitochondrial disorder [32], [33]. Recent reports emphasize a putative association between mitochondrial dysfunction and autism (for review see [34]) and highlight the role of brain energy metabolism dysfunction as an important target for future studies [35]. In ASD, as already emphasized for several neurodegenerative disorders [36], [37], [38], [39], mitochondrial dysfunction could be regarded as a secondary defect in brain energy metabolism.

They state that mitochondirial dysfunction is “secondary”, which I believe means they don’t see it as causative for autism. This is made more clear below:

The data reported here strongly support the view already stressed by others [20], [44] that systematic metabolic investigations are not contributive to the etiology of nonsyndromic ASD. On the other hand, early diagnosis and proper therapeutic intervention for some metabolic disorders causing nonsyndromic ASD may significantly improve the long-term cognitive and behavioral outcomes [20]. Therefore, a careful clinical evaluation, with cautious reappraisal of clinical signs, is crucial. Such a medical practice appears more reasonable than a costly systematic workup. Finally, a large population based prospective study assessing the benefits of routine metabolic screening in nonsyndromic ASD would be of great interest in the future to confirm our results.

They suggest that while discovering underlying metabolic disorders/dysfunctions can lead to beneficial treatments for those affected, they don’t shed light on the cause (etiology) of autism.

“Therefore, a careful clinical evaluation, with cautious reappraisal of clinical signs, is crucial. Such a medical practice appears more reasonable than a costly systematic workup. ”

I find the above very interesting. I’m sure that many in the alternative medical community would read that as approval of their less stringent diagnostic practices. To me it plays more into the idea that diagnosis of metabolic disorders can be as much an art as a science at times. To me, this means seeking out “one skilled in the art” (i.e. a metabolic specialist), rather than, say, a DAN doctor.

Here are a most of the references cited in the paragraphs above.

[30]Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, et al. (2005) Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 47: 185–189. Find this article online
[31]Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, et al. (2008) Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One 3: e3815. Find this article online
[32]Debray FG, Lambert M, Chevalier I, Robitaille Y, Decarie JC, et al. (2007) Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 119: 722–733. Find this article online
[33]Touati G, Rigal O, Lombes A, Frachon P, Giraud M, et al. (1997) In vivo functional investigations of lactic acid in patients with respiratory chain disorders. Arch Dis Child 76: 16–21. Find this article online
[34]Rossignol DA, Frye RE (2011) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry.
[35]Haas RH (2010) Autism and mitochondrial disease. Dev Disabil Res Rev 16: 144–153. Find this article online
[36]Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, et al. (2010) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802: 212-220. pp. 212–220.
[37]Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, et al. (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973–983. Find this article online
[38]Damiano M, Galvan L, Deglon N, Brouillet E (2010) Mitochondria in Huntington’s disease. Biochim Biophys Acta 1802: 52-61. pp. 52–61.
Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121: 493–499. Find this article online
[39] Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121: 493–499

Lack of Infection with XMRV or Other MLV-Related Viruses in Blood, Post-Mortem Brains and Paternal Gametes of Autistic Individuals.

7 Mar

Another paper has come out showing no link between XMRV (Xenotropic murine leukemia virus-related virus) and autism. A study last year (discussed on LBRB here) stated “These results imply that XMRV is not associated with autism.” In a study just released in the journal PLOS One, we see more evidence against such a link:

Lack of Infection with XMRV or Other MLV-Related Viruses in Blood, Post-Mortem Brains and Paternal Gametes of Autistic Individuals.

Lintas C, Guidi F, Manzi B, Mancini A, Curatolo P, Persico AM.

Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
Abstract

BACKGROUND: Autistic spectrum disorder (ASD) is characterized by impaired language, communication and social skills, as well as by repetitive and stereotypic patterns of behavior. Many autistic subjects display a dysregulation of the immune system which is compatible with an unresolved viral infection with prenatal onset, potentially due to vertical viral transmission. Recently, the xenotropic murine leukemia virus-related virus (XMRV) has been implicated in chronic fatigue syndrome (CFS) and in prostate cancer by several, though not all studies.

METHODOLOGY/PRINCIPAL FINDINGS: We assessed whether XMRV or other murine leukemia virus (MLV)-related viruses are involved in autistic disorder. Using nested PCR targeted to gag genomic sequences, we screened DNA samples from: (i) peripheral blood of 102 ASD patients and 97 controls, (ii) post-mortem brain samples of 20 ASD patients and 17 sex- and age-matched controls, (iii) semen samples of 11 fathers of ASD children, 25 infertile individuals and 7 fertile controls. No XMRV gag DNA sequences were detected, whereas peripheral blood samples of 3/97 (3.1%) controls were positive for MLV. CONCLUSIONS|

SIGNIFICANCE: No MLV-related virus was detected in blood, brain, and semen samples of ASD patients or fathers. Hence infection with XMRV or other MLV-related viruses is unlikely to contribute to autism pathogenesis.

The study concludes quite simply:

Our results, combined with those reported by Sutherfield et al [14], render XMRV contributions to autism highly unlikely. Nonetheless we cannot exclude that MLV-related viruses may play a role in rare cases.

Note that “Sutherfield” is a typo. Should be Satterfield. The reference is to the paper in Molecular Autism which was the topic of the discussion from last year that I linked to in the introduction to this piece.

Recent autism abstracts in Pubmed

17 Dec

Pubmed is an amazing resource. It is a Public Medical library of abstracts (and some articles) in the medical literature. I have a search set up so that I get emails with recent articles with the subject “autism”. I try to obtain some of the articles and discuss them here. This is not based on what I perceive to be the “best” or “most important” work, just what I want to explore. It has been difficult lately to go into depth in any articles and I find myself falling behind. For example, a couple of days ago the pubmed email had 29 abstracts in one day. Given that, here are a few recent abstracts that caught my eye:

Neonatally measured immunoglobulins and risk of autism.

Grether JK, Croen LA, Anderson MC, Nelson KB, Yolken RH.

California Department of Public Health, Richmond, California.
Abstract

Previous studies indicate that prenatal exposure to infections is a possible pathway through which autism spectrum disorders (ASD) could be initiated. We investigated whether immunoglobulin levels in archived specimens obtained from newborns subsequently diagnosed with ASD are different from levels in newborn specimens from controls. Children with ASD born in six California counties in 1994 were ascertained through records of the California Department of Developmental Services (DDS) and Kaiser Permanente; controls were randomly selected using birth certificates. Archived newborn blood specimens were obtained from the California Genetic Disease Screening Program (GDSP) for N = 213 cases and N = 265 controls and assayed to determine levels of total IgG, antigen-specific IgG to selected common pathogens, total IgM, total IgA, and C-reactive protein (CRP). We did not find measurable levels of total IgM or IgA in any neonate and measurable CRP was present in only a few. No antigen-specific IgG antibodies were elevated in cases compared to controls and total IgG levels were lower. In adjusted models, a 10-unit increase in total IgG yielded an OR = 0.72 (95% CI 0.56, 0.91); a significantly decreasing trend in risk of ASD was observed across increasing exposure quartiles of total IgG (P = 0.01). The finding of lower IgG in cases may indicate maternal immune dysfunction during gestation and/or impaired transplacental transfer of immunoglobulins. Further investigation of IgG levels in newborns and the mechanisms by which they might be associated with ASD are warranted.

This follows on some previous work on maternal antibodies and autism risk. In 2008, UC Davis published: Autism: maternally derived antibodies specific for fetal brain proteins and Johns Hopkins published: Antibodies against fetal brain in sera of mothers with autistic children. These studies looked at the blood sera from mothers of autistic children–sera taken long after the autistic child was born–and found that in some cases there were antibodies in the mothers’ sera against fetal brain proteins. The current study (Grether et al.) looked at blood spots of newborns–samples from the children rather than the mother. They did not find measurable levels of IgM or IgA in the infant’s blood spots. They also did not find c-reactive protein (a response to inflammation).

This study out of France looked at autistic children age 5 and again at age 8. They found that most children’s characteristics were stable, but some did show improvement (e.g. in speech level). What is interesting was the statement that the amount of intervention (hours) was not related to outcome.

Outcome of young children with autism: Does the amount of intervention influence developmental trajectories?

Darrou C, Pry R, Pernon E, Michelon C, Aussilloux C, Baghdadli A.

Montpellier I University, Montpellier III University, France.
Abstract

The study aims were to identify developmental trajectories of young children with autism and investigate their prognostic factors. The participants were 208 children, assessed first at the age of 5 years, followed longitudinally, and reassessed 3 years later. The children’s clinical characteristics and the interventions received were recorded. The results indicated two distinct outcome groups with more stability than change. When changes did occur, they pertained to symptom severity (which decreased) and speech level and adaptive behavior (which improved). A logistic regression analysis pointed out two main risk factors (symptom severity and speech level) and two main protection factors (communication skills and person-related cognition). Surprisingly, the amount of intervention (in terms of number of hours) was not related to outcome.

Given a recent discussion here on LeftBrainRightBrain on genetics, heritability, de-novo mutations and copy number variations (CNV’s), I found the following abstract interesting.

Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.

Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E, Gillberg C, Nordgren A, Uppströmer A, Anderlid BM, Nordenskjöld M, Schoumans J.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P?=?0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs. © 2010 Wiley-Liss, Inc.

I am always very interested in efforts to identify autistic adults. In the following study, from the Netherlands, the ADOS is explored for reliability in an group of “high functioning” autism.

Diagnosing Autism Spectrum Disorders in Adults: the Use of Autism Diagnostic Observation Schedule (ADOS) Module 4.

Bastiaansen JA, Meffert H, Hein S, Huizinga P, Ketelaars C, Pijnenborg M, Bartels A, Minderaa R, Keysers C, de Bildt A.

Social Brain Lab, Department of Neuroscience, University Medical Center, Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands

Abstract

Autism Diagnostic Observation Schedule (ADOS) module 4 was investigated in an independent sample of high-functioning adult males with an autism spectrum disorder (ASD) compared to three specific diagnostic groups: schizophrenia, psychopathy, and typical development. ADOS module 4 proves to be a reliable instrument with good predictive value. It can adequately discriminate ASD from psychopathy and typical development, but is less specific with respect to schizophrenia due to behavioral overlap between autistic and negative symptoms. However, these groups differ on some core items and explorative analyses indicate that a revision of the algorithm in line with Gotham et al. (J Autism Dev Disord 37: 613-627, 2007) could be beneficial for discriminating ASD from schizophrenia.

Lastly, here is an article which I believe may have already been discussed online previously. From PLoS One (which means the article is available free) Which Neurodevelopmental Disorders Get Researched and Why? I don’t think it will come as a surprise to many readers of LeftBrainRightBrain that autism research has seen a particularly large rise in the past decade.

Aim

There are substantial differences in the amount of research concerned with different disorders. This paper considers why.

Methods

Bibliographic searches were conducted to identify publications (1985–2009) concerned with 35 neurodevelopmental disorders: Developmental dyslexia, Developmental dyscalculia, Developmental coordination disorder, Speech sound disorder, Specific language impairment, Attention deficit hyperactivity disorder, Autistic spectrum disorder, Tourette syndrome, Intellectual disability, Angelman syndrome, Cerebral palsy, Cornelia de Lange syndrome, Cri du chat syndrome, Down syndrome, Duchenne muscular dystrophy, Fetal alcohol syndrome, Fragile X syndrome, Galactosaemia, Klinefelter syndrome, Lesch-Nyhan syndrome, Lowe syndrome, Marfan syndrome, Neurofibromatosis type 1, Noonan syndrome, Phenylketonuria, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Trisomy 18, Tuberous sclerosis, Turner syndrome, Velocardiofacial syndrome, Williams syndrome, XXX and XYY. A publication index reflecting N publications relative to prevalence was derived.

Results

The publication index was higher for rare than common conditions. However, this was partly explained by the tendency for rare disorders to be more severe.

Interpretation

Although research activity is predictable from severity and prevalence, there are exceptions. Low rates of research, and relatively low levels of NIH funding, characterise conditions that are the domain of a single discipline with limited research resources. Growth in research is not explained by severity, and was exceptionally steep for autism and ADHD.

A busy week in vaccine-injury news: the Cedillo appeal

4 Sep

The past week has had three somewhat major news events in the world of vaccine injury: the denial of the Cedillo appeal, the award of damages in the UK for an MMR case and the damages award in the Hannah Poling case. I thought I would write about them all, but the Cedillo appeal part is already long so I will leave the other subjects for another time.

The Cedillo Appeal

Kev blogged the denial as Cedillo appeal denied. I had blogged the hearing in June as Another appeal heard in the Autism Omnibus, then blogged the actual audio from the hearing as Audio of the Cedillo appeal part 1 and Audio of the Cedillo appeal part 2.

The arugument used in the Omnibus Autism Proceeding for MMR causing autism is basically the model that grew out of the work of Andrew Wakefield: that measles virus (MV) from vaccines persisted in the body, particularly in the digestive tract. Wakefield’s theory involved the MV infection causing intestinal permeability which allowed substances to “leak” out into the system (the “leaky gut” hypothesis). The Cedllio’s attorneys argued that the measles virus itself traveled to the brain, causing inflammation and autism.

This is not the first appeal for the Cedillo family, or for the test cases in the Omnibus. It is likely the last, however. The next step would be the U.S. Supreme Court. The Supreme Court would be unlikely to hear an appeal. The Supreme Court does not hear all the cases submitted, instead choosing to hear mostly cases which clarify points of law. The Cedillo appeal so far has not been about the laws for the most part but about the procedure of the case. One exception is the question of whether the correct standard was applied to reviewing the admissibility of the evidence. The Court used the Daubert standard, which the Cedillo’s attorneys argued was incorrect. This is not the first time the Court used Daubert, and it is not the first time the appeals court upheld it.

The other arguments made include whether the testimony and reports of Dr. Stephen Bustin should have been allowed. Dr. Bustin’s reports were obtained very shortly before the hearing and were based on closed documents from a U.K. proceeding on MMR and autism. The Cedillo’s attorneys argued that they were unable to prepare a counter argument to Dr. Bustin on short notice and that since they did not have access to the underlying data and documents. In a civil court, these arguments would have carried much weight. However, in the vaccine court, much flexibility is allowed. In this case, the Special Master allowed the evidence to be heard, and gave the Cedillo’s attorneys over a year to obtain the background data from the UK and mount a counter argument.

The Cedillo’s attorneys did not attempt to obtain the background data for the Bustin testimony in year that followed the hearing. Yes, it isn’t that they were unsuccessful, they didn’t try to obtain it. They stated that their consultants in the UK advised them that it was unlikely that they would be able to obtain the documents without the permission of the experts. However, Dr. Bustin gave his permission.

From the appeals court decision:

Petitioners considered making such a re-quest from the UK court, but never did so. They contend that British counsel informed them that it was unlikely that the UK court would permit disclosure of the expert reports without the consent of the experts, which peti-tioners stated that they could not obtain. But Dr. Bustin did consent to the release of his reports. Once his consent for the release of his reports had been obtained by the government, there is no reason why the data underlying his reports could not also have been requested

Dr. Bustin’s testimony focused on a critical part of the argument used to claim that MMR causes autism: the claimed presence of measles virus in the bodies of autistics like Miss Cedillo. Dr. Bustin is arguably the worlds top expert on PCR, the method used by the Unigenetics Laboratory to test tissue samples for measles virus. Dr. Bustin discussed at length multiple reasons why the Unigenetics Laboratory results were not reliable.

A few points to be made here.

(1) The Cedillo’s attorneys presented an expert (Dr. Kennedy) to claim that the Unigenetics laboratory was reliable. Dr. Kennedy also had worked on the UK litigation and Dr. Kennedy’s underlying data were also under seal in that litigation. In other words, the Cedillo’s attorney’s were asking that the Special Master apply one standard to the government’s witness (rejecting his report without the underlying data) while applying the exact opposite standard to their own witness (Dr. Kennedy, who also didn’t have the underlying data).

(2) Michelle Cedillo was one of three “test cases” used to test the question of “general causation”. The other two children used as test cases did not have evidence of persistent measles virus in their bodies.

There is only one paper with reliable data showing the presence of measles virus in the tissues of an autistic child. This paper came out after the Cedillo hearing. The paper: Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study. In that study they found measles virus in one autistic child, and in one non-autistic “control”. The Cedillo’s attorney’s argued that this was “significant new evidence” that showed the reliability of the Unigenetics laboratory.

I found it very odd that a paper titled “Lack of association between Mealses Virus Vaccine and Autism with Enteropathy” would be used as evidence for an association between measles virus vaccine and autism. But the argument is that this paper validates the Unigenetics laboratory as being able to produce reliable results. The argument is not valid, and the court did not agree with it. The work done by Unigenetics on Miss Cedillo was performed in 2002. The research on the paper was performed much later, after significant criticism was already levied against Unigenetics. Quite simply put, it is possible that Unigenetics “cleaned up its act” by the time of the recent paper.

(3) It was noted that the arguments about Dr. Bustin’s testimony were essentially moot, as the Special Master would have come to the same decision without his testimony.

(4) It was also noted that the appeals court had already decided on Dr. Bustin’s testimony in an appeal mounted by the attorneys for the Hazelhurst family (another of the Omnibus test cases).

The Cedillo’s attorneys further argued that it was unfair that evidence was brought in from the other “test case” hearings (Hazelhurst and Snyder). The appeals ruling noted that the Cedillo hearing was not a stand-alone proceeding. As a test case in an Omnibus Proceeding, evidence from all the test cases would be used to answer the question of general causation. I was surprised at the time of the appeal that the Cedillo’s attorneys were arguing that they were not actively monitoring the other test case hearings. What, in the end, is the point of an Omnibus Proceeding or a “petitioners steering committee” of the petitioners are not acting in some way as a group?

The Cedillo’s attorneys argued that the Special Master did not give enough weight to Miss Cedillo’s doctor, Dr. Krigsman, who stated that her condition was caused by MMR. The fact is that the Special Master rejected Dr. Krigsman’s argument with good cause:

He [the special master] also concluded that Dr. Krigsman’s opinion should be rejected because 1) he relied on the discredited Unigenetics testing in forming his opinion, 2) he misunderstood Michelle’s medical history and his testimony was inconsistent with her medical records, and 3) his conclusion that Michelle suffered from chronic gastrointestinal inflammation was substantially out-weighed by Michelle’s medical records and the testimony of the government’s experts.

The Cedillo’s attorneys argued that sufficient weight was not given to Miss Cedillo’s other physicians whom, they assert, associated her condition with the MMR vaccine:

Petitioners cited nine notations in Michelle’s records from eight individuals, including four physicians who treated Michelle and four non-physicians who exam-ined Michelle, in which the treating physicians mentioned her vaccinations, as support for the proposition that these individuals concluded that her autism was caused by her MMR vaccine.

The appeals court disagreed:

The Special Master did not err in failing to afford sig-nificant weight to the opinions of Michelle’s treating physicians. As the Special Master observed in his deci-sion, in seven of the nine notations, the physician was simply indicating an awareness of a temporal, not causal, relationship between the fever Michelle experienced after her MMR vaccine and the emergence of her autistic symptoms sometime thereafter. Initial Decision, slip op. at 100. In one of the other notations, the physician sim-ply noted that an exemption for Michelle from vaccination requirements could be arranged. In the other notation, the physician speculated that Michelle’s fevers might have caused her neurological abnormalities. However, he expressly stated that it would be “difficult to say” whether this was “a post-immunization phenomenon, or a separate occurrence.” Id. at 100. Thus, “none of the treating physicians concluded that the MMR vaccine caused Michelle’s autism.” Final Decision, 89 Fed. Cl. at 176. The Special Master

In the end, the appeals court decision takes on the arguments by the Cedillo’s attorneys point by point and refutes them. The closest the Cedillo’s attorneys got to making a point stick was in the case of Dr. Bustin’s testimony, which the appeals court stated:

We agree with petitioners that the government’s fail-ure to produce or even to request the documentation underlying Dr. Bustin’s reports is troubling, but we think that in the circumstances of this case, that failure does not justify reversal.

The fact of the matter is, the petitioners in general, and the Cedillo’s in specific, did not have a good case for MMR causing autism. The mechanism they proposed was not sound, the data they had was poor and incomplete and the experts speaking for the government were excellent and refuted the petitioner’s arguments. The Omnibus cases were, as the Special Masters noted, not close.