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Autism research and other musings

Paul Whiteley
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  • December 12, 2016
  • 05:37 AM

Maternal immune activation (MIA) and Old World monkeys

by Paul Whiteley in Questioning Answers

Old World monkeys detailed in the title of this post, specifically refers to a type of animal called a rhesus macaque who were the 'participants' of choice as detailed in a recent study by Destanie Rose and colleagues [1] looking at a concept called maternal immune activation (MIA).Those who followed this blog down the years will no doubt have seen me discuss MIA before in the context of autism and/or schizophrenia (see here for example). The basic theory is that whilst in-utero and enjoying approximately nine months in a warm and comfortable environment with a reprogrammed maternal immune system to stop a mother's body from 'rejecting' a developing foetus, infections encountered by the mother at critical periods of pregnancy might themselves or through their effects on the maternal immune system, have the ability to 'affect' offspring outcomes in a variety of ways. The majority of work on the concept of MIA has been in smaller animals such as rodents, so the inclusion of rhesus macaques is an important step as it was in other work with the immune system and autism in mind (see here).So, take 21 pregnancy rhesus macaques and give them either "three injections over 72 hours of poly I:C-LC [an immune stimulant], a double stranded RNA analog (viral mimic), or saline as a control." Said injections were given either "near the end of the first trimester or near the end of the second trimester" to see whether timing of immune stimulation might be important. Macaque offspring were subsequently born and followed for about 4 years. Blood samples were collected from offspring "at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function." At the same time, the behaviours of monkey offspring were also analysed to see if there were any effects from MIA exposure.Results: behaviour did seem to be affected by MIA exposure, particularly stereotyped behaviours, noted to be a core feature of autism. Similarly, researchers reported some important immune system 'changes' associated with MIA exposure: "elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α" at 1 year of age. Immune system changes were also noted longer-term at 4-years: "the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13." Although being careful not to generalise too much when it comes to immune system markers and what they mean for pro- or anti-inflammatory signals, the leaning towards the production of Th-2 cytokines is typically linked to atopy and 'the promotion of IgE and eosinophilic responses in atopy.' The authors - including some notable names from the MIND Institute - conclude by suggesting that: "Data from this study suggests long-term behavioral and immune activation was present in offspring following MIA."Accepting that animal models of something like MIA are not necessarily the same as human MIA and its responses, this is interesting work. If one however accepts the data on something like vaccine function being modelled in animals (see here for example) is akin to what happens in people, real people, there is some added strength to the information published by Rose and other groups on how MIA may indeed be a relevant factor when it comes to immune function potentially affecting offspring behaviour and development.This research also intersects with quite a lot of other peer-reviewed science talking about how (human) pregnancy infection does seem to be related to offspring risk for conditions such as autism (see here). That various immune-related conditions such as asthma in mothers might also 'prime' for offspring neurodevelopmental issues is another important strand of research potentially pertinent to this area (see here). And then also there is the idea of an 'inflammatory autism subtype' (see here) also previously suggested continuing the important theme of immune function and behaviour/development being linked. There are, as you can see, quite a few potentially important connections that can be made between the Rose results and other data on MIA and offspring development.Oh, and I'll be coming to the recent paper by Zerbo and colleagues all in good time...----------[1] Rose DR. et al. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun. 2016 Nov 19. pii: S0889-1591(16)30522-0.----------Rose, D., Careaga, M., Van de Water, J., McAllister, K., Bauman, M., & Ashwood, P. (2016). Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2016.11.020... Read more »

  • December 10, 2016
  • 05:28 AM

"Are we expecting too much from the extreme male brain theory of autism?"

by Paul Whiteley in Questioning Answers

The title of this post reflects the commentary published by Andrew Whitehouse [1] (open-access) discussing the meaning of the findings reported by Kung and colleagues [2] who quite categorically stated that there was: "No relationship between prenatal androgen exposure and autistic traits" in their study.OK, androgen exposure and psychology basically refers to the extreme male brain theory and autism which suggests that the so-called over-representation of autism in males is potentially down to hormone exposure (testosterone). The theory implies that androgen exposure at critical points in early development are skewing brain development towards a more 'male brain'. The definition of a male brain: well, apparently men are better systemisers than empathisers (better engineers that priests, I assume). The extreme male brain (EMB) hypothesis is an extension of the 'Theory of Mind' (ToM) stuff, which quite a few years back suggested that those diagnosed as being on the autism spectrum have greater difficulties in decoding mental states such as intents and desires. Grand psychological theories at their very finest you might say.The problem is that whilst ToM and the EMB theory made great psychological textbook reading (certainly in their heyday between the mid-1980s up to the late 1990s) and have spawned a whole industry around testing and teaching ToM for example, the scientific evidence for these concepts being exclusively and universally attributable to the great heterogeneity that is autism is not actually all that great. A shocker I know; and don't even ask about how comorbidity around autism might also be pretty important to such psychological concepts (see here and see here for example).Whitehouse - who himself has done some research in this area - talks quite a bit about the hows and whys of quite a few negative findings when it comes to the EMB theory (yes, there are quite a few) and what perhaps needs to be done to "advance beyond this stalemate" in relation to the EMB theory and autism.  His suggestion: "future research must first understand how the prenatal hormone environment relates to individual behavioural dimensions, and then incorporate this knowledge into the investigation of links with the more aetiologically and phenotypically complex profile of ASD [autism spectrum disorder]."These are wise words indeed but I'd suggest this perhaps applies to any 'theory' in relation to autism, psychological, biological or genetic. Indeed, I believe that other authors (see here) have already staked their claim on how using the word 'autism' as a starting point for anything other than a descriptive label probably isn't going to move autism research along any time soon; autisms people, autisms. The challenge is also one of moving away from generalisations; so talking about male and female brains is probably about as useful as talking about left and right-sided brains. Indeed, I'll refer you to some discussions about 'gender brains' between the main proponent of the EMB theory and a psychologist a few years back (see here and see here) that kicked up some scientific dust.I personally do think there is something in the findings looking at androgen levels and cognitive styles in the same way that there is something in most (replicated) peer-reviewed research when it comes to autism. But as Prof. Whitehouse indicates, it's probably going to be more relevant to some on the autism spectrum than others, and even then, disentangling the 'cognitive' structure of autism is going to be important [3]. The days of grand over-arching psychological theories about autism do seem to be riding off into the scientific sunset as the huge diversity and 'burden' of over-represented comorbidity start to come into plain sight. And certainly I don't think it's too rude to end with the words 'about time too'.To close, I hark back to simpler days or should that be to a simpler future when Buck Rogers showed the 25th Century how to boogie. Tell him what you think Twiki.----------[1] Whitehouse AJO. Commentary: Are we expecting too much from the extreme male brain theory of autism? A reflection on Kung et al. (2016). J Child Psychol Psychiatry. 2016 Dec;57(12):1463-1464.[2] Kung KT. et al. No relationship between prenatal androgen exposure and autistic traits: convergent evidence from studies of children with congenital adrenal hyperplasia and of amniotic testosterone concentrations in typically developing children. J Child Psychol Psychiatry. 2016 Dec;57(12):1455-1462.[3] Happé F. et al. Time to give up on a single explanation for autism. Nat Neurosci. 2006 Oct;9(10):1218-20.----------Whitehouse AJ (2016). Commentary: Are we expecting too much from the extreme male brain theory of autism? A reflection on Kung et al. (2016). Journal of child psychology and psychiatry, and allied disciplines, 57 (12), 1463-1464 PMID: 27859346... Read more »

  • December 9, 2016
  • 05:53 AM

'Big data' Taiwan and schizophrenia risk

by Paul Whiteley in Questioning Answers

Today I bring the findings reported by Chou and colleagues [1] (open-access available here) to the blogging table and how the research might of the Taiwan National Health Insurance Database (NHIRD) brought it's 'big data' ("n = 23 422 955") to bear on the question: what is the risk of developing schizophrenia where one or more first-degree or other relatives are affected?The answer: "Having an affected co-twin, first-degree relative, second-degree relative, or spouse was associated with an adjusted RR [relative risk] (95% CI) of 37.86 (30.55-46.92), 6.30 (6.09-6.53), 2.44 (1.91-3.12), and 1.88 (1.64-2.15), respectively. Compared with the general population, individuals with one affected first-degree relative had a RR (95% CI) of 6.00 (5.79-6.22) and those with 2 or more had a RR (95% CI) of 14.66 (13.00-16.53) for schizophrenia."To translate the science-talk: if one twin is diagnosed with schizophrenia, there is a hugely increased risk of the other twin also being affected. If a mother or father, sister or brother, or your child(ren) are diagnosed with schizophrenia, there is an enhanced risk but nothing like the risk to twins. As you move outwards to other outlying family members (uncles, aunts, grandparents, etc) affected, your risk continues to diminish albeit still noticeable. Interestingly, when it comes to spouses (husband or wife), there is a small but increased risk that if they are diagnosed with schizophrenia so the other partner is at some small, enhanced risk. This tallies with the concept of assortative mating [2] but does not necessarily rule out other shared non-genetic factors either.The final sentence in that quote provides some evidence for a cumulative effect too. So if one of your close family members is diagnosed with schizophrenia, so the risk to yourself might be heightened. If two or more close family members are diagnosed, the relative risk to yourself jumps quite a bit more."A family history of schizophrenia is therefore associated with a higher risk of developing schizophrenia, mood disorders, and delusional disorders. Heritability and environmental factors each account for half of the phenotypic variance of schizophrenia."To close, Yoda don't like seagulls...----------[1] Chou IJ. et al. Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families. Schizophr Bull. 2016 Nov 21. pii: sbw159.[2] Parnas J. Assortative mating in schizophrenia: results from the Copenhagen High-Risk Study. Psychiatry. 1988 Feb;51(1):58-64.----------Chou IJ, Kuo CF, Huang YS, Grainge MJ, Valdes AM, See LC, Yu KH, Luo SF, Huang LS, Tseng WY, Zhang W, & Doherty M (2016). Familial Aggregation and Heritability of Schizophrenia and Co-aggregation of Psychiatric Illnesses in Affected Families. Schizophrenia bulletin PMID: 27872260... Read more »

  • December 8, 2016
  • 05:51 AM

Prescription medication use and autism: good medicines management required

by Paul Whiteley in Questioning Answers

"Prescription drug use and polypharmacy rates among adults with ASD [autism spectrum disorder] are substantially higher than those in an age-, sex-, and race-matched cohort of adults without ASD."That sentence taken from the paper by Rini Vohra and colleagues [1] (open-access available here) is probably not likely to win any 'novel findings of the year' awards given the already quite voluminous data published on the medication use and autism (see here for example). What gives the Vohra data a bit of an edge is that: (a) they included data for some 1700 adults with autism "matched 1:3 with adults without autism", (b) data were derived from administrative health insurance claims databases in the United States ("Medicaid programs"), and (c) they examined "the rates of prescription drug use, general polypharmacy, and psychotropic polypharmacy among adults" thus were able to detail not just psychotropic medication use but also that for other, more general conditions too.Their findings were stark. Accompanying that opening sentence on medication use and autism, authors reported that: "Annually, almost 75% of adults with ASD had >20 prescription drug claims compared with 33% of adults without ASD." That's more than 20 prescription medication claims per year.Further: "Other than psychotropics, many adults with ASD used medical prescription drugs such as antimicrobials (47%), dermatologic agents (48%), respiratory agents (38%), gastrointestinal agents (31%), alternative medications (25%), antiparkinsonian agents (22.6%), antihyperlipidemics/statins (7.3%), and immunologics (2.0%)." So when we start talking about the label of autism not appearing in some sort of diagnostic vacuum, and particularly that various medical comorbidity seem to be 'over-represented' when it comes to autism (see here), this is reflected in the large burden of medication being dispensed. If readers trawl through the adjusted odds ratios (AORs) generated when those with autism were compared with controls (Table 1), you'll note that many classes of medicine were more frequently prescribed to those with autism.  And where medicines were less frequently prescribed to the autism group, there were some potentially telling signs too: analgesics (used for pain relief), antidiabetics and antimicrobials. One could argue that maybe those diagnosed with autism have less need of things like pain relief or antibiotics or less likely to need antidiabetic medicines. One might however similarly argue that their medical and healthcare screening services could perhaps be 'less rigorous' than those not diagnosed with autism too, potentially as a result of various factors (see here).Onwards: "Adults with ASD and a psychiatric comorbidity such as an adjustment disorder (26%), mood disorder (31%), or schizophrenia (32%) had significantly high rates of psychotropic polypharmacy." I probably don't need to say much more about this sentence aside from the fact that mood disorder including things like depression are not uncommon diagnoses alongside autism (see here). The links with the schizophrenia spectrum are also not to be underestimated (see here).Finally: "Older age, female gender, White race, and presence of three or more comorbid conditions among adults with ASD is significantly associated with using six or more prescription drug classes per year." This sentence is not a roadmap to predicting who will need what medicines when it comes to autism but does provide some important information. There is for example, a woeful lack of research on autism in a longitudinal sense (see here) despite the topic of ageing and autism being debated time and time again. Inevitably as people age, their medication requirements are likely to change (increase?); this is as true for autism as it is for the not-autism population.I included the words 'good medicines management required' in the title of this post because, as you can see, the level of prescription medicines use when it comes to autism can be high and one needs to be careful that medicines are appropriate, monitored regularly and don't interact with one and another. Given what is also known about psychotropic medicines in particular in terms of potential side-effects (see here and see here for examples), the onus is surely on prescribers to keep an even closer eye on those with autism who are being medicated under their care. Medication is a part of life when it comes to autism. I base that last sentence on the wealth of data, peer-reviewed and otherwise, that has been published on this topic. I'm sure nobody particularly likes the idea of medication particularly when it comes to autism and certainly nobody should like the idea that some people on the autism spectrum are receiving quite a lot of prescription medicine concurrently and over quite long periods of time. But here's the thing, medication (generally) serves an important purpose. In the case of the antiepileptics/anticonvulsants it can be life-saving. Where mood disorders such as depression are being pharmacologically treated, it can be life-saving. Until, science is able to get a better idea of why some many conditions/labels seem to be over-represented when it comes to autism, medication is often all that it can offer at the moment...----------[1] Vohra R. et al. Prescription Drug Use and Polypharmacy Among Medicaid-Enrolled Adults with Autism: A Retrospective Cross-Sectional Analysis. Drugs Real World Outcomes. 2016 Nov 21.----------Vohra R, Madhavan S, Sambamoorthi U, StPeter C, Poe S, Dwibedi N, & Ajmera M (2016). Prescription Drug Use and Polypharmacy Among Medicaid-Enrolled Adults with Autism: A Retrospective Cross-Sectional Analysis. Drugs - real world outcomes PMID: 27873285... Read more »

  • December 7, 2016
  • 01:36 PM

Pregnancy folic acid and offspring autism systematically reviewed

by Paul Whiteley in Questioning Answers

"A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy."That rather long quote taken from the paper published by Yunfei Gao and colleagues [1] (open-access) opens today's post and provides a welcome [peer-reviewed] overview of where science is up to when it comes to the effects (or not) of pregnancy folic acid supplementation on 'risk' of offspring autism. I say 'where the science is up to' but at the same time note that the various searches of databases for material relevant to this topic/review was carried out up to the end of 2014. There have been other reports since that date including other reviews [2]...Folic acid or folate in the context of autism has been a recurrent research theme down the years. Outside of the protective effects of pregnancy folate use with regards to reducing the risk of offspring neural tube defects (NTDs), the suggestion that pregnancy folic acid may confer a protective effect against offspring autism has been highlighted in several studies (see here).Gao et al trawled the research literature and "included randomized controlled trials (RCTs), cohort studies, and case control studies that examined the association between folic acid supplementation during pregnancy and neurodevelopment/autism in the offspring children." As per that lengthy opening sentence from their paper, the authors found data that on the whole suggested that folate supplementation was protective rather than harmful when it came to offspring developmental outcomes. Given that most/many pregnant women are already taking folic acid during pregnancy to counter the risk of NTDs, this is good news indeed.Without giving any undue weight to those studies that have perhaps not been so enthusiastic about the link between pregnancy folate use and offspring autism risk (see here) I do think there are words of caution in this area too. We're still for example, waiting for research to be published that was raised at this years IMFAR event in relation to folic acid and autism (see here). Indeed, in my discussion of that so-far-unpublished work, I mentioned that the genetics of folic acid metabolism also needs to be further inspected when it comes to autism (see here) and that screening for particular issues linked to folate might be something to consider for people on the autism spectrum and their significant others (see here). Both these areas are potentially relevant to that recent chatter on how folinic acid might be useful for some aspects of some autism (see here)."Large scale RCTs with validated diagnosis and high follow up rate are needed in order to produce robust evidence regarding the effects of folic acid supplementation in pregnancy on fetal neurodevelopment" conclude the authors. Yes, we need more investigation of this area - including what effect certain medicines used during pregnancy might have had on folate levels -  but for now, the data seems to side with a protective effect of folate supplementation in pregnancy when it comes to offspring risk of autism or related neurodevelopmental issues.----------[1] Gao Y. et al. New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children – A Systematic Review. PLoS ONE. 2016; 11(11): e0165626.[2] DeVilbiss EA. et al. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr. 2015 Sep 14;114(5):663-72.----------Gao Y, Sheng C, Xie RH, Sun W, Asztalos E, Moddemann D, Zwaigenbaum L, Walker M, & Wen SW (2016). New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review. PloS one, 11 (11) PMID: 27875541... Read more »

  • December 6, 2016
  • 04:05 AM

Infections treated with anti-infective agents linked to schizophrenia?

by Paul Whiteley in Questioning Answers

Identify everyone born in Denmark between 1985-2002. Identify those treated "in the primary care setting" for an infection. Identify those diagnosed with schizophrenia and affective disorders. Look-see whether there is an overlap between infection or treated infection and schizophrenia / affective disorders. Report results.That's basically the study published by Köhler and colleagues [1] (a name that has appeared on this blog before) who concluded that: "Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors."Mention of Denmark as being the source material for such a discovery means, yet again, that those various Scandinavian population registries are proving their 'big data' scientific worth. Indeed, such resources really do put countries such as Blighty to shame insofar as tracking the health of the Nation and at the same, providing science with lots and lots of research nuggets.Taking into account various "confounders", authors report that alongside a possible connection between infection or treatment for infection being 'associated' with schizophrenia / affective disorders there was "a dose-response and temporal relationship" further substantiating their findings. Indeed, those who had to be hospitalised for infection (a serious infection then) were at much greater risk of subsequently being diagnosed with schizophrenia or affective disorders. This tallies with other research on this topic (see here).One more thing: "The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment." Interesting. This suggests that bacterial infections or their treatments, e.g. antibiotics seem to be important factors in relation to the subsequent risk of schizophrenia and/or affective disorders. Again, this is not the first time that this point has been raised (see here and see here) and provides some corroborative evidence as to why the microbiome was mentioned by authors in relation to possible mechanisms to account for their findings.I could start talking about how this research is further evidence for a role for the immune system and/or inflammatory processes in relation to psychiatric labels (see here for example) but you've probably heard it all before I'm sure. What we are also starting to understand with some confidence, is that infection and the effects of it's treatment might go way beyond just the somatic...----------[1] Köhler O. et al. Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr Scand. 2016 Nov 21.----------Köhler O, Petersen L, Mors O, Mortensen PB, Yolken RH, Gasse C, & Benros ME (2016). Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta psychiatrica Scandinavica PMID: 27870529... Read more »

  • December 5, 2016
  • 03:58 AM

Double-blind randomised, placebo-controlled trial of vitamin D in autism

by Paul Whiteley in Questioning Answers

It was inevitable ("it is your destiny") that I would formulate a post about the paper published by Khaled Saad and colleagues [1] reporting results based on "a double-blinded, randomized clinical trial (RCT)" looking at the potential usefulness of a vitamin D supplement on "the core symptoms of autism in children." Inevitable because the peer-reviewed research literature looking at the sunshine vitamin/hormone in relation to autism is getting rather voluminous (see here and see here for examples) with the promise of lots more to come (see here). The fact that the name Saad in relation to this area of autism research has appeared before on this blog (see here) indicates that this researcher/research group are no strangers to this area of autism science.First, thanks to Alex for the Saad paper. And so... utilising the premier research design, where 109 children* (aged 3-10 years old) diagnosed with an autism spectrum disorder (ASD) were randomly allocated to receive vitamin D drops - "300 IU [international units] vitamin D3/kg/day, not to exceed 5,000 IU/day" - or a placebo drops over 4 months and then tested blind "by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC)" before and after their vitamin D or placebo, some interesting results emerged. Their trial and protocol, by the way, was also registered. [*Actually, 120 children were initially allocated to vitamin D or placebo but 11 were lost to follow-up or discontinued participation in the study.]Results: well first and foremost the tenet 'do no harm' seemed to be adhered to as we are told that "vitamin D was well tolerated by the ASD children" at least for the study duration. This is particularly important in light of that case report a few weeks back talking about vitamin D toxicity in the context of autism (see here). Indeed: "The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study" kinda shows that authors were probably mindful of possible toxicity issues [2] alongside wanting to get a little more information about baseline vs. endpoint levels of the stuff. Having said all that the use of vitamin D was not completely side-effect free as 5 children taking the vitamin D drops reported symptoms such as "skin rashes, itching, and diarrhea."Further: "The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group." Scores on the CARS (Total scores) showed a "significant decrease" in the vitamin D group compared with the group taking the placebo drops. This was in the direction of vitamin D supplementation positively impacting on the presentation of autistic symptoms. Scores on the ATEC also showed something akin to improvement for those taking the vitamin D drops. As one might expect, measured levels of vitamin D - "serum levels of 25 (OH)D" - rose in the vitamin D supplemented group compared to those in the placebo group.These are interesting results providing some of the first double-blind RCT findings in relation to vitamin D supplementation and autism. I particularly like the fact that alongside well-validated instruments such as the CARS for 'measuring autism', the authors also included the ATEC, an instrument that I have growing fondness for (see here). They also measured functional vitamin D levels (albeit via an ELISA assay - I'd prefer via mass spec!) so it's not difficult to see that minus any unknown variables, the behavioural changes seem to match the biological changes to vitamin D status.There is more to do and indeed, more research in this area is already underway. Larger groups of participants still following that gold standard research methodology will give a more accurate picture and perhaps provide some details about potential best responders to such an intervention (something already hinted at in the Saad data). And then there is the question of 'how' vitamin D might be affecting the presentation of [some] autism. Well, far be it from me to speculate too much, and also taking into account what Saad et al have to say on this matter, I suggest that we might learn a thing or two from looking at vitamin D use in other areas of medicine (see here) and taking things from there...For now, here is what the UK Government says about vitamin D and the population at large although not everyone is convinced...Music: Kate Bush and This Woman's Work....----------[1] Saad K. et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry. 2016 Nov 21.[2] Vogiatzi MG. et al. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014 Apr;99(4):1132-41.----------Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, Bjørklund G, Jia F, Urbina MA, Abo-Elela MG, Ahmad FA, Abd El-Baseer KA, Ahmed AE, & Abdel-Salam AM (2016). Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. Journal of child psychology and psychiatry, and allied disciplines PMID: 27868194... Read more »

Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, Bjørklund G, Jia F, Urbina MA, Abo-Elela MG.... (2016) Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. Journal of child psychology and psychiatry, and allied disciplines. PMID: 27868194  

  • December 3, 2016
  • 05:23 AM

Parent-mediated interventions for young children with autism meta-analysed

by Paul Whiteley in Questioning Answers

Do not mess with  Lois.Today I'm posting on the topic of the paper by Rose Nevill and colleagues [1] concluding: "that while most outcome domains of parent-delivered intervention are associated with small effects, the quality of research is improving."Parent-mediated interventions in relation to autism have been covered on this blog quite recently (see here) accompanied by that 'super-parenting' headline fail. Such approaches work on the idea that helping parents to "develop strategies for interaction and management of behaviour" [2] might be one route of early intervention when it comes to autism. The research road has however not been smooth when it comes to this class of intervention (see here) and despite some positives (see here) has perhaps not been the overwhelming success that many had hoped for.Nevill and colleagues reviewed 19 trials of parent-mediated interventions for autism ("randomized clinical trials") looking at various outcomes in relation to core symptoms of autism and aspects such as communication and cognitive functions. The results kinda reiterate what we already know that so far, parent-mediated interventions aren't really cutting the statistical mustard when it comes to outcomes and important statistics related to effect sizes. Indeed, the [weighted] Hedge's g statistics produced by the authors on the cumulative data in this area can, at best, be described as 'modest' (and I mean at best). As a comparison, have a look at the Hedge's g stats produced by a meta-analysis of the placebo response when it came to autism [3]: "a moderate effect size for overall placebo response (Hedges' g=0.45, 95% confidence interval (0.34-0.56), P<0.001)" (based on "25 data sets (1315 participants)"). This bearing in mind that the parent-mediated intervention trials don't usually include a placebo condition (and indeed, typically don't even blind - how could you?)I don't want to poo-poo all of this area of autism science because it may still be pretty important. A few things do however worry me about the attention here based on the ideas that parent-child interactions are somehow the be-all-and-end-all of autism (also harking back to the bad 'ole days) and that in these times of continued cost-savings and austerity, parents are being expected to carry out the same services as other professionals. On that first point focused on parent-child interactions, I've always been a little cautious about what this means. Certainly in light of the primary focus on this blog, looking at genetics, epigenetics and biochemistry when it comes to autism, parent-mediated interventions are to be seen as a reactive strategy attempting to deal with 'symptoms' not necessarily causes. Yes, I know 'symptoms' are what parents and other family members see and deal with day in day out, but I'm wondering how successful parent-mediated intervention would be if used in the context of autism secondary to an inborn error of metabolism for example? Surely it makes more sense to spend a little more time ruling out some of the potential reasons why autism or particular autistic features might come about (i.e. screening - see here and see here for some other examples) rather than universally providing a parent-mediated intervention manual and hoping for the best? I might also add that a greater recognition that among 'the autisms' (see here) there may be some important waxing and waning of presentation(s) (see here) potentially influenced by things like the presence of comorbidity too reiterates that every person is an individual and set manuals on parent-child interactions don't necessarily cover all that heterogeneity. And there's also the suggestion that some parent-mediated intervention options are also seemingly failing when it comes to important comorbidities such as anxiety (knowing how disabling these can be) as being something else that needs to be kept in mind.We'll have to see how this area develops further but for now, I don't think anyone can seriously say the existing research on this topic has shown anything like the successes that everyone hoped for. And whilst we should celebrate the fact that "the quality of research is improving" I'm not sure one can blame the limited success of such an approach on previous poor quality research.To close, today is a really, really big day for some of my brood who have their 1st Dan black belt grading. After several years of training, hard work and effort pertinent to their voyages through Shotokan karate it all comes down to examination this evening. Thanks and credit need to go to their Sensei for all their efforts in getting them this far, as well as a certain practitioner who is Shotokan YouTube royalty. Whoever you are, thank you.----------[1] Nevill RE. et al. Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder. Autism. 2016. Nov 14.[2] Oono IP. et al. Parent-mediated early intervention for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2013 Apr 30;(4):CD009774.[3] Masi A. et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015 Sep 22;5:e640.----------Nevill, R., Lecavalier, L., & Stratis, E. (2016). Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder Autism DOI: 10.1177/1362361316677838... Read more »

  • December 2, 2016
  • 04:18 AM

The prebiotic galactooligosaccharide (B-GOS) and autism: just add to poo(p)

by Paul Whiteley in Questioning Answers

Yes, it is childish but...With all the continued chatter on a possible role for the collected gut microbiota - those wee beasties that inhabit our deepest, darkest recesses - in relation to some autism (see here for example), the paper by Roberta Grimaldi and colleagues [1] (open-access available here) provides yet more potentially important information.So, poo(p) samples were the starring material in the paper - "obtained from three non-autistic children and three autistic child donors"- and specifically what happened when something called B-GOS "a prebiotic galactooligosaccharide" was added to samples following their journey through a "Three stage continuous culture gut model system" otherwise known as an artificial gut. Said gut model based at Reading University has already been the topic of other news (see here).As well as looking at the initial bacterial profile of those stool samples, researchers plotted the changes to the stool's inhabitants (or what was left of the stool) over the course of B-GOS addition, as well as looking at things like the "production of SCFAs [short-chain fatty acids] in the fermentations" and other metabolites via the gold-standard chemical analytical technique called 1H-NMR (see here for more details).Results: "Consistent with previous studies, the microbiota of ASD [autism spectrum disorder] children contained a higher number of Clostridium spp. and a lower number of bifidobacteria compared to non-autistic children." With the addition of B-GOS to the 'mixture', researchers reported on a significant increase in bifidobacterial populations at the different stages of their gut model and in samples from both those with autism and those without autism. Such "bifidogenic properties of B-GOS" are not unheard of.As to the metabolites of those bacteria present in the poo(p) samples, there were some interesting knock-on effects noted in both raw and B-GOS supplemented samples. "Our data show a lower concentration of butyrate and propionate in autistic models, compared to non-autistic models, but nodifferences in acetate before adding B-GOS into the system." Propionic acid (propionate) has some research history with autism in mind (see here). Butyric acid (butyrate) is something of a rising star in quite a few domains, having also been mentioned in the context of autism too (see here). Indeed it's interesting to note that B-GOS administration "mediated significant production of... butyrate... simulating the transverse and distal colon respectively. There was no effect on propionate." The findings of lower starting levels of butyrate in samples from children with autism were also substantiated by the NMR analyses undertaken. Increases in butyrate and changes to various other metabolites ("increasing ethanol, lactate, acetate and butyrate and decreasing propionate and trimethylamine") were also noted via this analytical method for this group.A long quote coming up: "This in vitro study showed promising and positive results in that supplementing the microbiota of ASD children with 65%B-GOS may manipulate the gut bacterial population and alter metabolic activity towards a configuration that might represent a health benefit to the host. However, further work will be required to assess such changes in an in vivo human intervention study."Just before anyone makes a run on B-GOS or any similar product however, I do need to stress a few important points. First, this was a study of poo(p) samples from 3 autistic children compared with samples from 3 non-autistic children. Aside from the small participant numbers, we don't know anything about participants' various comorbidities (although we know they were "free of any metabolic and gastrointestinal diseases") and only limited information on their dietary habits and medication history. Second, poo(p) was the target material included for analysis and what happened when B-GOS was supplemented during the journey through the artificial gut model. This study said nothing about what happens when real people with autism take B-GOS orally for example, and how it might affect gut bacterial populations and metabolites as it progresses down a real gastrointestinal (GI) tract. This also includes a lack of information on any potential side-effects in a real-world situation. We are also assuming that any supplement survives the stomach. There is quite a bit more to do in this area.But for now, I stick to the idea that the Grimaldi paper provides some potentially important information and certainly, some new routes/methods for further study of the link between prebiotics, probiotics and synbiotics in the context of the gut microbiota and autism...----------[1] Grimaldi R. et al. In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS Microbiol Ecol. 2016 Nov 16. pii: fiw233.----------Grimaldi R, Cela D, Swann JR, Vulevic J, Gibson GR, Tzortzis G, & Costabile A (2016). In vitro fermentation of B-GOS: Impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children. FEMS microbiology ecology PMID: 27856622... Read more »

  • December 1, 2016
  • 03:57 AM

Dietary fibre deficiency and gut barrier integrity

by Paul Whiteley in Questioning Answers

"Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium."So said the findings reported by Mahesh Desai and colleagues [1] meriting an editorial in the publishing journal [2] as the sentiments of 'eating your greens' applies to some rather interesting [mouse] findings.Fibre (UK spelling) comes in various different forms typically categorised as soluble and insoluble depending on their relationship with water. Using a "gnotobiotic mouse model" - where mice were "colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria" - Desai et al reported on the effects of different diets with different fibre content. Their results make for important reading as a fibre-deprived gut was associated with the rise of some rather potent bacteria that seemed to enjoy dining out on the "colonic mucus barrier, which serves as a primary defense against enteric pathogens." Yes, mice gut barriers - or some of their components at least - were being eaten by the very bacteria they contain. Enjoy your lunch.I'm not dwelling too much on the Desai findings, bearing in mind their focus on mice not humans, but I do want to raise a couple of potentially relevant points. First is the focus on the intestinal barrier and how that so-called 'leaky gut' seems to show a connection to dietary fibre intake. Yet more research bringing this woo-like term in from the scientific cold (see here). Next is the idea that if the Desai results are transferable from mouse to humans, they could be relevant to quite a lot of people who perhaps don't enjoy as much dietary fibre as they should. Further, there may be particular groups of people who might be particularly prone to a poor diet [3] (see here too) where the already discussed term 'leaky gut' is also relevant (see here); also bringing in the idea of a role for those trillions of wee beasties (the gut microbiota) that call us home.I'll be watching for how this research area pans out...----------[1] Desai MS. et al. A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell. 2016 Nov 17;167(5):1339-1353.e21.[2] Gazzaniga FS. & Kasper DL. Veggies and Intact Grains a Day Keep the Pathogens Away. Cell. 2016 Nov 17;167(5):1161-1162.[3] Bandini LG. et al. Changes in Food Selectivity in Children with Autism Spectrum Disorder. J Autism Dev Disord. 2016 Nov 19.----------Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B, Wilmes P, Stappenbeck TS, Núñez G, & Martens EC (2016). A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell, 167 (5), 1339-2147483647 PMID: 27863247... Read more »

Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A.... (2016) A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell, 167(5), 1339-2147483647. PMID: 27863247  

  • November 30, 2016
  • 04:10 AM

Restless leg syndrome in parents of children with autism

by Paul Whiteley in Questioning Answers

The findings reported by Maureen Russell and colleagues [1] provide some blogging fodder today and the observation that: "Biological caregivers of children with ASD [autism spectrum disorder] demonstrated a high prevalence of RLS [Restless Legs Syndrome] symptoms and poorer mental health."OK, I know some people might be asking 'just what is Restless Legs Syndrome'? It is a recognised condition complete with 'disease' title (Willis-Ekbom disease). Symptoms, as the name suggests, centre on 'an overwhelming, irresistible urge to move the legs'. But things might not just stop at 'jittery legs' when it comes to this condition, as various other parts of the body can also be involved and indeed, affect important functions such as sleep.Russell et al surveyed 50 biological caregivers (parents) of children diagnosed with an autism spectrum disorder (ASD) with regards to sleep habits "that included RLS as determined by four questions." They also "compared the sleep quality and daytime behaviors of children with ASD in caregivers with and without symptoms of RLS."They observed that just over a fifth of their caregiver cohort "fit the criteria for RLS symptomatology." They also reported that those 'biological caregivers' who reported RLS symptoms also reported "poorer mental health" based on responses to the "Medical Outcomes Survey (MOS) 12-Item Short Form (SF-12)." When it came to offspring parameters, authors reported that: "Caregivers with RLS described more night waking and greater internalized behavior problems in their children with ASD than the caregivers without RLS." They interpret this 'association' in the context that there is a degree of heritability attached to RLS and some of those sleeping issues noted in offspring could mean that the symptoms of RLS are also present in children diagnosed with ASD too.Noting the relatively small scale of the Russell study in participant number terms, the very preliminary method of reporting on mental health and the fact that there isn't a single test for RLS, these are interesting findings. I note the lead author has her PhD online (see here) showing how this research fits into a larger scheme of work on sleep and quality of life in caregivers of children with autism.Looking at the Russell findings in the context of 'hows and whys' there are some potentially important correlations that might be noteworthy. RLS has been linked with the presentation of attention-deficit hyperactivity disorder (ADHD), a not insignificant comorbidity noted in quite a bit of autism (see here). I don't want to make any connections where none might exist but it is reasonable to assume that an over-represented occurrence of ADHD in autism could be important. Insofar as the heritability of ADHD specifically across families, there is more to do in this area but it's not unheard of for ADHD symptoms to be present in other family members including parents. This could impact on the results reported by Russell et al.Although certain medicines have been associated with the symptoms of RLS, there is also a body of peer-reviewed science suggesting that a deficiency in iron might also be important [2]. There is still a degree of debate specifically as to how iron deficiency might 'cause' RLS but one of the primary lines of thinking revolves around how iron is an important co-factor for the biological reactions that turn the amino acid tyrosine [eventually] into the neurotransmitter dopamine. Again, minus any 'I know all the answers' sentiments, iron levels in relation to autism have been a source of some investigation down the years (see here). Some researchers have also talked about maternal iron intake potentially affecting the 'risk' of offspring autism too (see here) (with appropriate caveats).Whatever the reason(s) to account for the Russell findings, there is a requirement for further research in this area, for a start to assess just how prevalent RLS might be in both people diagnosed on the autism spectrum and their significant others. Knowing how much comorbidity seems to follow a diagnosis of autism (see here) I wouldn't be surprised to see yet another connection; this one however, might provide some rather important clues as to overlapping genetics and biology...Music, and Gotye still has an amazing song...----------[1] Russell M. et al. Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. J Clin Sleep Med. 2016 Oct 28. pii: jc-00043-16.[2] Li X. et al. Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla. Sleep Med. 2016 Jun;22:75-82.----------Russell M, Baldwin C, McClain D, Matthews N, Smith C, & Quan SF (2016). Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine PMID: 27855729... Read more »

Russell M, Baldwin C, McClain D, Matthews N, Smith C, & Quan SF. (2016) Symptoms of Restless Legs Syndrome in Biological Caregivers of Children with Autism Spectrum Disorders. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. PMID: 27855729  

  • November 29, 2016
  • 06:24 AM

Publication bias and autism research

by Paul Whiteley in Questioning Answers

The title of the paper by Konstantin Mechler and colleagues - "Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis" [1] - provides some discussion today. Drawing on the ideas that publication bias and/or the so-called 'file-drawer problem' - terms that refer to the non-publication of study results potentially skewing the collected scientific opinion in a particular area - might also extend into autism research too, Mechler et al detail results according to their analysis of a particular trial registration database called: is one of the premier 'tell everyone about your trial' databases designed to provide a bit of transparency to science. The idea is that you register (pre-register hopefully) your research study, register what you are going to do and how, and importantly, provide some details about what your are going to be assessing (outcomes). Some of the research that I've been involved with has a mention in this database (see here) with more to come in future times. Once your entry is in it kinda stops you from making any major 'alterations' to your study potentially based on the results you get, whilst at the same time also getting quite a few prods to post things like your raw study results for everyone to see and analyse as they wish. And believe me, they are quite a persistent bunch over at!So Mechler and colleagues "searched for all completed randomized controlled clinical trials investigating interventions in ASD [autism spectrum disorder] and their results made public." They looked at how many trials had been submitted and how many reported results. Where no results were available on or on other 'scientific databases' or after "enquiries of the responsible parties or sponsors listed", the authors listed the trial as 'not published'.The good news: 60% of trials (n=30) were published in the peer-reviewed domain. The not-so-good news was that reported in the opening sentence of this post as some 40% of trials (n=20) fell into that not published category. Authors also mention that some 1600 participants were included in those not published trials, inferring that data on quite a few people diagnosed with an ASD and agreeing (themselves or by proxy) to participate in research remain 'missing' in a research sense."The results emphasize the serious issue of publication bias. The large proportion of unpublished results precludes valuable information and has the potential to distort evidence for treatment approaches in ASD." This an important point in any area of science but perhaps more so when you have a label like autism and a whole host of 'unknowns' about the aetiology, nature and course of presentation. I would like to think that there were some rational reasons why so many trials were missing results (studies having to be halted/stopped, collaborations breaking down, resources being exhausted, etc) but there is always going to suspicion around the non-publication of such results particularly the idea that 'researchers or funders did not get the results they hoped for'. Other discussions on this topic outside of autism (see here) point to the failure to publish being tantamount to an ethical breach. Strong words indeed.Although Mechler et al focused on data from the initiative I'd perhaps suggest that the issues they discuss probably go a lot deeper as a function of there being quite a few other databases where such trial information is held and listed. Perhaps also just as concerning is the fact that many other pieces of research are not listed anywhere when it comes to trial registration and therefore have even less 'motivation' to publish results or are perhaps more likely to be subject to 'alteration' in terms of methodology or outcome(s). All of which contributes to the possible tarnishing of science and the reporting of said science and paves the way for criticism.Music, it's not Mother's Day or anything like that but do give her a call from time-to-time and treat your mother right...----------[1] Mechler K. et al. Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International Journal of Methods in Psychiatric Research. 2016. Nov 9.----------Mechler K, Hoffmann GF, Dittmann RW, & Ries M (2016). Defining the hidden evidence in autism research. Forty per cent of rigorously designed clinical trials remain unpublished - a cross-sectional analysis. International journal of methods in psychiatric research PMID: 27862603... Read more »

  • November 28, 2016
  • 04:23 AM

On moving off the autism spectrum

by Paul Whiteley in Questioning Answers

The paper by Nahit Motavalli Mukaddes and colleagues [1] provides some important, if small-scale, information when it comes to that still controversial term - optimal outcome - with the diagnosis of autism in mind. Optimal outcome basically refers to a particular 'type' of autism whereby following a definite diagnosis of autism or autism spectrum disorder (ASD), a later re-evaluation of signs and symptoms reveals that diagnostic thresholds are subsequently not reached and/or exceeded and hence, the criteria for autism are not fulfilled.I say this is a controversial term because it is. Still after quite a bit of peer-reviewed published research saying 'yes, it exists' (and alongside quite a few manifestations of autism) coupled with quite a bit of research talking about different developmental trajectories accompanying different 'types' of autism (see here) the old 'they weren't really autistic' phrase still comes out time and time again. And with it, children/adults who were diagnosed with autism are doubted to have been actually autistic. The skills of the professionals who made the diagnosis are doubted. The parents and significant others who most likely initiated the screening and diagnosis of autism are doubted. All of this seemingly to uphold the 'lifelong' tag that accompanies quite a bit of discussion about autism. Not a great state of affairs eh?Work by Mukaddes et al has previously made an appearance on this blog (see here) talking about possible predictors of optimal outcome. This time around they aimed to "assess the autism symptoms and other psychiatric disorders in a group of children with a past history of autism." Their group, comprised of 26 who "lost the diagnosis of autism two to eight years previously", were assessed for autism - DSM-5 autism no less - together with various other psychometric/behavioural schedules.Results: "None of the participants met criteria for an autism diagnosis." What this means is that for their cohort, 'loss' of a diagnosis of autism was not some short-term thing. But be careful here, as I remind you that DSM-5 criteria "were used for [a] diagnosis of ASD" for autism and the emerging data suggesting that DSM-5 is already likely to move quite a few people off the autism spectrum compared with previous diagnostic schedules (see here). Indeed, I wonder how many of their cohort might be labelled with SCD instead?When it came however to looking at other psychiatric/behavioural labels, being an optimal outcomer with autism in mind did not necessarily mean symptom-free: "81% had a present psychiatric disorder based on the K-SADS. ADHD [attention-deficit hyperactivity disorder], specific phobia and Obsessive Compulsive Disorder (OCD) were the most common disorders." This finding is interesting. Interesting because it does not necessarily tally with other work on this topic (see here) but at the same time, reiterates that a diagnosis of autism rarely exists in a diagnostic vacuum (see here) (and that includes past diagnoses of autism). That ADHD in particular, is a label of growing importance to quite a few cases of autism should also be mentioned (see here) as should be the 'effects' that such a label has been linked with (see here)."It is crucial to maintain psychiatric follow up of children who move-off ASD." Wise words from Mukaddes and colleagues but given the state of things here in Blighty, with continued austerity and long, long wait lists for assessments (see here), I don't really have a great deal of confidence that removal from the autism spectrum is going to prompt much in the way of follow-up. Indeed, going back to the question of whether optimal outcomers might nevertheless hit SCD - 'autism lite' -  diagnostic thresholds, I'm not even sure that those fitting into the SCD description are going to receive anything like the services and support they will still no doubt require. I do hope that I am wrong but...----------[1] Mukaddes NH. et al. What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study. Pediatrics Int. 2016. Nov 12.----------Motavalli Mukaddes, N., Mutluer, T., Ayik, B., & Umut, A. (2016). What Happens to Children Who Move off the Autism Spectrum? A Clinical Follow-Up Study Pediatrics International DOI: 10.1111/ped.13202... Read more »

  • November 26, 2016
  • 05:33 AM

Acetylation focus over methylation in autism epigenetics?

by Paul Whiteley in Questioning Answers

The paper by Wenjie Sun and colleagues [1] (open-access) provides the blogging fodder for today's post and although based on the science of epigenetics, the usual suspect - DNA methylation - gives way to another concept: histone acetylation with autism in mind. Before heading into the paper myself, I'll draw your attention to some other write-ups of the study including a hat-tip to Jeff Craig and his piece on the topic (see here).So histone acetylation... I've covered the subject before on this blog (see here) but basically DNA, the stuff that carries the genetic blueprint, complexes with histones to form something called nucleosomes. It's a combination likened to thread wrapped around a spool. Continuing that thread wrapped around a spool analogy, protruding threads called histone tails can be modified in a chemical sense (via processes such as acetylation where an acetyl group is added or deacetylation where one is removed) which can subsequently affect genetic transcription.Still with me? Good. Sun and colleagues set out to look at histone acetylation in the context of autism; specifically in post-mortem brain samples donated from those deceased who were diagnosed with autism and whether they might show some important changes based on the use of "a histone acetylome-wide association study (HAWAS)."Specific areas of the brain were assessed using the HAWAS approach - "prefrontal cortex (PFC), temporal cortex (TC), and cerebellum (CB)" - and researchers were looking for a specific type of acetylation mark called H3K27ac linked to gene activation. Based on brain samples from 94 participants ("45 ASD [autism spectrum disorder], 49 control"), a few details emerged:Despite the expected heterogeneity across the presentation of autism in terms of whether the diagnosis of autism was syndromic (secondary to an existing condition) or non-syndromic (idiopathic), the authors reported that approaching 70% of the autism cases "shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex." In other words, a not uncommon molecular signature in relation to histone acetylation seemed to be present in quite a few of the participant samples included for study.Although one needs to be a little cautious about making grand, sweeping claims about how such an 'acetylome signature' comes about, the authors reported "that ASD-specific differential acetylation is driven mostly by.. factors such as environmental influences, SNPs in trans (at a different locus), indels, and larger chromosomal variants." Note the term 'environmental influences' (something I'll come back to shortly).When it came to what types of genes were potentially being 'affected' by acetylation, the authors report on quite a diverse spread "involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity." Epilepsy and autism is a recurrent theme in the research and clinical literature (see here for example) so there are no great surprise there. 'Immunity' and autism is something else that keeps cropping time and time and time again (see here).I appreciate that the authors also acknowledge that whilst autism was the focus on the current work, they do also mention: "By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases." This opens up the idea that various different psychiatric/behavioural labels might show 'overlap' when it comes to the histone acetylome too.Interesting stuff by all accounts. I do like the idea that autism research is continuing to look at other areas of gene expression outside of just structural issues to the genome being linked to the condition (or should that be plural). Aside from the fact that people don't walk around with their genes permanently stuck in the 'on or off position' in every tissue all the time, the whole epigenetics field is a welcome complement to more traditional genomics. The focus on gene expression being potentially 'modifiable' might also reunite genetics and environment too (see here).Criticisms of the Sun study? Well, brain samples from the deceased are a precious resource but not without complications when it comes their use for science (see here). I appreciate that we don't have the technology to look at histone acetylation in real-time or real-life yet with the brain in mind but one has to be cautious about the results from the brains of the deceased who may have passed away for many different reasons. There is also the temptation to move the whole epigenetics 'thing' towards acetylation on the basis of such research, but the methylome still remains potentially important (see here) and probably for more than one reason (see here). Perhaps soon we'll see a study looking at more than one epigenetic factor with autism in mind?Going back to the concept of 'environmental influences' mentioned in the Sun paper, there are some potentially important repercussions from study results such as these. As with the concept of DNA methylation, one of the important concepts linked to the science of epigenetics is that such chemical alterations affecting the expression of DNA are potentially modifiable. This could mean that particular environmental factors working at critical periods might affect acetylation and methylation patterns and onward the expression of certain genes pertinent to the presentation of something like autism or at least facets of autism. The other scenario is that certain 'conditions' or 'interventions' might 'reverse such changes. On that last point, I might bring in some previous discussions on this blog in relation to something called HDAC (histone deacetylase) inhibitors (see here) that, as their name suggests, have the ability to inhibit the action of histone deacetylases (they remove acetyl groups). Various classes of medicines are classed at HDAC inhibitors including something called valproic acid which has some autism research history (see here for example). It's not therefore beyond the realms of possibility that the actions of certain medicines or other non-genetic factors with an influence on acetylation could be a source for further research in this area.Independent replication is the next stage... Read more »

Sun, W., Poschmann, J., Cruz-Herrera del Rosario, R., Parikshak, N., Hajan, H., Kumar, V., Ramasamy, R., Belgard, T., Elanggovan, B., Wong, C.... (2016) Histone Acetylome-wide Association Study of Autism Spectrum Disorder. Cell, 167(5), 1385-2147483647. DOI: 10.1016/j.cell.2016.10.031  

  • November 25, 2016
  • 03:49 AM

Screening for coeliac disease in autism

by Paul Whiteley in Questioning Answers

"The overall CD [coeliac disease or celiac disease depending on where you live] prevalence was 2.62%, which is statistically significant higher to that reported in the Italian paediatric population... If replicated, these data suggest the importance of regular screening for CD in young patients with ASD [autism spectrum disorder]."Those were some of the findings/conclusions reported in the paper by Sara Calderoni and colleagues [1] (open-access) and with them, some important data quite pertinent to some of the primary interests of this blog and indeed, my research career.Coeliac disease is an autoimmune condition (NOT AN ALLERGY!) whereby genetics, biology and environment converge on how dietary gluten - the stuff in foods like bread, pasta and cereals - is not necessarily a great idea for everyone. The ideas that: (a) a diagnosis of autism or ASD is seemingly protective of nothing and (b) all that chatter about gluten potentially affecting 'some' autism [2] plays heavily into the quite longstanding research history probing any connection between CD and autism. The question of whether CD is over-represented in autism has had many twists and turns including famously being studied by a certain H Asperger charcter.Calderoni and colleagues, drawing on data from a country with more than it's fair share of interest in CD, retrospectively examined data for over 380 children diagnosed with an ASD who had also been screened (serologically) for possible CD. Such screening included "determination of the titres of Anti-Gliadin (AGA) immunoglobuline (Ig)A and IgG, Anti-Transglutaminase (anti-tTG) IgA, and Anti-Endomysium (EMA) IgA antibodies." Further examinations of medical records for those screening positive to some of these parameters was undertaken to see "whether the CD diagnosis had been subsequently confirmed by paediatric gastroenterologists."Results: ten participants were identified "with CD or with positive CD serology." The authors provide some details about these 10 children - "six males and four females, with mean age of 41 months." They make an important point about their 'prevalence of CD' figures: "the prevalence of “CD patients plus screening detected individuals with both anti-tTG and EMA positivity” was 2.62% (10/382 subjects)." This based on the fact that not everyone of these 10 children had formally received a diagnosis of CD from a gastroenterologist for various reasons. Interestingly too, when it came to the data about whether CD was symptomatic i.e. outside of just being serologically present whether the corresponding symptoms of CD were present, the authors conclude that quite a few "had no symptoms or risk factors correlated with CD at the time of the serological screening." Finally, compared with other population data on CD prevalence, researchers suggested that CD may be yet another over-represented comorbidity following a diagnosis of ASD.Interestingly, the authors suggest that their figures on CD in ASD might be an underestimate. They say this based on the idea that for example, generally low IgA levels is an issue when it comes to CD screening and onwards the possibility of false-negative results [3]. Although not necessarily widespread, low levels of IgA or IgA deficiency is not an unstrange finding in relation to some 'types' of autism [4].I can't argue with the Calderoni findings and the potential importance of preferential screening for CD when a diagnosis of autism is received [5] . What I might add however, is that more and more science and clinical practice is understanding that there are grey areas between coeliac disease and not coeliac disease (see here) and such notions on 'non-coeliac gluten/wheat sensitivity' might open up issues with gluten for quite a few more people diagnosed on the autism spectrum (see here). Indeed, as I always seem to do when talking about such issues, I would refer you to my 'Gluten and autism: probably not coeliac disease but...' post (see here) as representing an important step in our understanding of this topic. That and the idea that birds of an autoimmune feather tend to flock together, and other potential associations are opened up as a result of any links between coeliac disease and autism (see here)...But whatever you do, don't mention leaky gut as potentially also being involved (see here) (whisper it instead).----------[1] Calderoni S. et al. Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder. Italian Journal of Pediatrics. 2016; 42: 98.[2] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.[3] Prince HE. et al. Immunoglobulin A (IgA) Deficiency and Alternative Celiac Disease-Associated Antibodies in Sera Submitted to a Reference Laboratory for Endomysial IgA Testing. Clinical and Diagnostic Laboratory Immunology. 2000;7(2):192-196.[4] Wasilewska J. et al. Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Archives of Medical Science : AMS. 2012;8(2):324-331.[5] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.----------Calderoni, S., Santocchi, E., Del Bianco, T., Brunori, E., Caponi, L., Paolicchi, A., Fulceri, F., Prosperi, M., Narzisi, A., Cosenza, A., Tancredi, R., & Muratori, F. (2016). Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder Italian Journal of Pediatrics, 42 (1) DOI: 10.1186/s13052-016-0308-x... Read more »

Calderoni, S., Santocchi, E., Del Bianco, T., Brunori, E., Caponi, L., Paolicchi, A., Fulceri, F., Prosperi, M., Narzisi, A., Cosenza, A.... (2016) Serological screening for Celiac Disease in 382 pre-schoolers with Autism Spectrum Disorder. Italian Journal of Pediatrics, 42(1). DOI: 10.1186/s13052-016-0308-x  

  • November 24, 2016
  • 05:48 AM

Breastfeeding and autism (or autistic traits) continued?

by Paul Whiteley in Questioning Answers

"After adjustment for several confounders, longer duration of breastfeeding was independently associated with better cognitive development and with fewer autistic traits."So said the paper by Olivier Boucher and colleagues [1] communicating findings based on the examination of data from "the INMA Project, a Spanish multicenter birth-cohort study" (an initiative that has cropped up on this blog before).Including over 1300 children who were subject to a battery of psychometric and behavioural assessments, researchers set about examining how various scores might be 'associated' with breastfeeding patterns: "Duration of any, predominant, and exclusive breastfeeding." The results as I've mentioned, seemed to show something of a connection between breastfeeding and particularly when it came to 'autistic traits' as assessed by the Childhood Autism Spectrum Test (CAST). I'll leave readers to draw their own conclusions about the relevance of this finding. Insofar as the more general conclusion on breastfeeding potentially aiding offspring cognitive development, well, let's just say that this has previously been mentioned before in the research literature (see here).Having talked about breastfeeding in the context of autism before on this blog (see here) I don't really want to head too far into the collected literature in this area alongside the other aspects/discussions that it draws in. All I will say is that the relationship between breastfeeding patterns and offspring autism/autistic traits is not likely to be straight-forward [2] (few things with regards to autism research ever are) and there could even be occasions when breast milk might not be the preferred option* (see here) (*I should reiterate that I am not providing medical or clinical advice on this blog). There are, for example, a multitude of potentially confounding variables that could impact on any association between the two; not least that early manifestations of offspring autism might already be present and impacting on the ease of breastfeeding practices during the very earliest days and weeks of infancy. I'm not gonna say too much more on this topic at this time but will perhaps return to the subject in future posts.----------[1] Boucher O. et al. Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatr Res. 2016 Nov 15.[2] Penn AH. et al. Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr. 2016 Feb;62(2):317-27.----------Boucher O, Julvez J, Guxens M, Arranz E, Ibarluzea J, Sánchez de Miguel M, Fernández-Somoano A, Tardon A, Rebagliato M, Garcia-Esteban R, O'Connor G, Ballester F, & Sunyer J (2016). Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatric research PMID: 27846197... Read more »

Boucher O, Julvez J, Guxens M, Arranz E, Ibarluzea J, Sánchez de Miguel M, Fernández-Somoano A, Tardon A, Rebagliato M, Garcia-Esteban R.... (2016) Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatric research. PMID: 27846197  

  • November 23, 2016
  • 05:29 AM

ADHD symptoms not methylphenidate treatment might prime for psychotic events

by Paul Whiteley in Questioning Answers

"This study does not support the hypothesis that MPH [methylphenidate] increases risk of incident psychotic events. It does indicate an increased risk of psychotic events before the first prescription of MPH, which may be because of an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment."The results published by Man and colleagues [1] (open-access) sit right with me. I say that on the basis that previous research suggesting that attention-deficit hyperactivity disorder (ADHD) may 'prime' someone for an elevated risk of developing psychosis (see here) has potentially received some welcome substantiation. That MPH might not be the bogeyman that some people might think (see here too) is also an important part of the Man findings (minus any charges of me providing medical or clinical advice on this blog... I'm not).The Man paper is open-access but a few choice details are worthwhile mentioning:Based on data from the "Clinical Data Analysis and Reporting System (CDARS)" an initiative based in Hong Kong, researchers set about identifying those "aged 6–19 years who received at least one prescription of MPH with at least one psychotic disorder and/or hallucination diagnostic code (psychotic events) during the study period (January 2001 to December 2014)." Given that only MPH and atomoxetine are seemingly licensed in the Hong Kong for "the treatment of ADHD", the authors were able to focus specifically on MPH quite easily.Although over 20,000 patients were in receipt of MPH prescriptions, only data for 103 participants were used in the study as a result of that diagnosis of a psychotic/hallucinatory condition. Most were male and 76 out of the 103 participants had "a clinical ADHD diagnosis."Researchers looked at MPH treatment and those psychotic/hallucinatory events taking into the account timing and including "a 90-day pre-exposure period" representing a period before MPH use (see here).Results: "The primary analysis indicated no statistically significant association between MPH treatment and occurrence of incident psychotic events." But, when compared with baseline data, there did seem to be something to see during that pre-exposure period (before MPH) and incident psychotic event(s). Ergo, something other than MPH use seemed to be linked to the experience of psychosis and we therefore head back to the idea that ADHD as one reason for MPH use might have some quite profound implications for future mental health.There is still quite a bit more to do in this area as per more longitudinal research with greater participant numbers. I might also draw your attention to Table 2 of the Man paper (see here) examining other 'psychiatric comorbidities' when it came to those participants experiencing a psychotic episode. The list of potential correlates is interesting in light of other work (see here).Whilst MPH comes out of such research with more than a whiff of roses, it is perhaps important to understand that medicines, all medicines come with potential side-effects and that includes MPH. Nevertheless, the idea that the benefits of controlled use of MPH might trump the risk of serious psychiatric side-effects such as psychosis is something that needs to be said and with it, a realisation that treating/managing the signs and symptoms of ADHD early, might have more profound repercussions for those diagnosed...----------[1] Man KKC. et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Translational Psychiatry. 2016; 6: e956.----------Man, K., Coghill, D., Chan, E., Lau, W., Hollis, C., Liddle, E., Banaschewski, T., McCarthy, S., Neubert, A., Sayal, K., Ip, P., & Wong, I. (2016). Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system Translational Psychiatry, 6 (11) DOI: 10.1038/tp.2016.216... Read more »

Man, K., Coghill, D., Chan, E., Lau, W., Hollis, C., Liddle, E., Banaschewski, T., McCarthy, S., Neubert, A., Sayal, K.... (2016) Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Translational Psychiatry, 6(11). DOI: 10.1038/tp.2016.216  

  • November 22, 2016
  • 04:01 AM

Probiotics and 'subclincial' psychological symptoms: meta-analysed

by Paul Whiteley in Questioning Answers

I'm gonna be fairly brief today and draw your attention to yet another systematic review and meta-analysis this time looking at how "probiotic supplementation can have a positive effect on mood and psychological symptoms such as depression and anxiety." [1] Probiotics by the way, include a variety of bacteria and related lifeforms that are thought to confer some health advantage.The review/re-analysis by Jennifer McKean and colleagues found 7 studies on this topic in the peer-reviewed research literature, that overall "showed that supplementation with probiotics resulted in a statistically significant improvement in psychological symptoms... compared with placebo." Personally, I wasn't surprised at these findings having covered a few bits of science on probiotics and psychology before on this blog (see here for example). Some recent discussions on how probiotics might be a possible 'stress-reliever' (see here) also add to this area.I know some people are still a little sceptical of the whole 'gut-brain' thing (i.e. what goes on in the gut might have the ability to influence what goes on the grey/pink matter floating in the skull) and all the associated 'hype' that has accompanied the new science around the gut microbiota including the use of probiotics. There is lots more to do in this area; also overlapping with how other interventions may more detrimentally affect the trillions of bacteria that call us home and onwards may have 'psychological consequences' too (see here).But it is getting rather more difficult not to think that there may be some important processes at work in these times of psychobiotics [2]...----------[1] McKean J. et al. Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis. J Altern Complement Med. 2016 Nov 14.[2] Dinan TG. et al. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6.----------McKean J, Naug H, Nikbakht E, Amiet B, & Colson N (2016). Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis. Journal of alternative and complementary medicine (New York, N.Y.) PMID: 27841940... Read more »

  • November 21, 2016
  • 05:48 AM

On C-reactive protein and bipolar disorder

by Paul Whiteley in Questioning Answers

"CRP [C-reactive protein] concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania."So said the systematic review and meta-analysis published by Brisa Fernandes and colleagues [1] who surveyed the peer-reviewed literature on the topic of "measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls" and arrived at their conclusions based on an analysis of some 2000 people diagnosed with bipolar disorder (BD). CRP by the way, a member of the pentraxin family, is the molecule of choice when it comes to looking at response to inflammation. BD, previously known as manic depression, is a condition characterised by periods of depression and mania.Continuing an important theme in psychiatry - that the immune system or expression of the immune system whether in terms of genetics or biology, seems to show some important associations with behaviour (see here for example) - the Fernandes paper represents important work. Of course it's not the first time that CRP levels and bipolar disorder have been mentioned on this blog (see here) but the 'collecting' of results based on the use of systematic review and meta-analysis this time around strengthens the association between these variables.Where next I hear you ask? Well, the idea that CRP levels might be linked to cases of BD needs further research not least to ensure that certain over-represented medical comorbidity linked to BD are not an interfering variable when it comes to CRP levels (see here). The findings should also perhaps be seen in a larger context where CRP levels have been reported in other psychiatric / behavioural labels (see here). The non-specificity of CRP (i.e. not tied to just one label) also has implications for the idea that many different psychiatric / behavioural labels might show overlapping features (see here) for example.With no medical or clinical advice given or intended, there is also the intriguing idea that interventions targeting specific immune function findings may also have behavioural implications (see here for example). This alongside the idea that some medicines intended for the treatment or management of aspects of BD may already have some 'immune-modulating' actions (see here) potentially tied into their potential efficacy (or not). Again, further research is very much implied.----------[1] Fernandes BS. et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016 Nov 9. pii: S2215-0366(16)30370-4.----------Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, Jacka F, Köhler CA, Karmakar C, Carvalho AF, & Berk M (2016). C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. The lancet. Psychiatry PMID: 27838212... Read more »

Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, Jacka F, Köhler CA, Karmakar C, Carvalho AF.... (2016) C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. The lancet. Psychiatry. PMID: 27838212  

  • November 19, 2016
  • 05:13 AM

Low gestational age is associated with risk for autism

by Paul Whiteley in Questioning Answers

The results published by Robert Joseph and colleagues [1] provide some blogging fodder today, observing that as part of the ELGAN (Extremely Low Gestational Age Newborns) Research Study, gestational age might matter when it comes to offspring risk of autism spectrum disorder (ASD).Gestational age is a measure of how far along a pregnancy is but in the context of the Joseph study refers to premature birth or those "born at least 3 months early." Researchers included data for nearly 1000 children born extremely premature using a prospective (rather than retrospective) methodology who, at age 10, were "evaluated for ASD and ID [intellectual disability]." They also took into account various other 'pregnancy information' derived from both medical records and interviews with mums. This included instances of cervical-vaginal ‘infection’ among other things.The results: over 90% of their cohort were assessed for autism/ASD and ID. Rates of ASD alone (without ID) were 3.2%. Some 3.8% of participants screened positive for autism and ID and 8.5% of participants presented with ID but not autism. Whilst these autism (with or without ID) rates might seem high, I'm not actually convinced that they are 'significantly higher' than that suggested in modern times (see here). The authors also noted that: "The lowest gestational age category (23-24 weeks) was associated with increased risk of ASD+/ID+... and ASD+/ID-."Also: "Maternal report of presumed cervical-vaginal ‘infection’ during pregnancy was associated with increased risk of ASD+/ID+." The sorts of things included under the heading of cervical-vaginal infection were "bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4) or other/unspecified infection (n=43; e.g., chlamydia, trichomonas or herpes, etc.)."I agree with the authors that "low gestational age is associated with increased risk for ASD" and this research does seem to tally with other studies on this topic (see here for example). The one caveat I do want to make however is that the absolute numbers of children diagnosed with autism (with or without ID) were quite low (27 and 32 children respectively out of a total of 840) and somewhat dwarfed in comparison to those presenting with ID without autism (71 children out of 840). Still, preferential screening for autism and ID might be implied from these results; assuming that is, that the screening instrument in question is up to the job [2].As to potential mechanisms of effect... well, it's rather difficult to pin any 'excess autism risk' to any one mechanism in light of the various factors that can accompany prematurity. Aside from the immaturity of various biological system associated with premature birth (including the brain), the obvious effect of a reduced birth weight is something to consider (see here). I am also interested in the idea that infection (using the term quite broadly) during pregnancy might also impact on offspring autism risk in light of other data (see here). Specific pathogens during pregnancy affecting offspring developmental risks have already made a mark on the peer-reviewed research literature (see here for example) and could provide a template for the processes pertinent to infection plus prematurity too.----------[1] Joseph RM. et al. Extremely low gestational age and very low birth weight for gestational age are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation.  American Journal of Obstetrics and Gynecology. 2016. Aug 13.[2] Kim SH. et al. Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm. J Pediatr. 2016 Nov;178:101-107.e2.----------Joseph, R., Korzeniewski, S., Allred, E., O’Shea, T., Heeren, T., Frazier, J., Ware, J., Hirtz, D., Leviton, A., & Kuban, K. (2016). Extremely low gestational age and very low birth weight for gestational age are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation American Journal of Obstetrics and Gynecology DOI: 10.1016/j.ajog.2016.11.1009... Read more »

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