Wednesday, 28 June 2017

On your marks, GETSET...

I don't doubt that the article published by Lucy Clark and colleagues [1] (open-access) on the topic of testing "the efficacy and safety of graded exercise delivered as guided self-help" in the context of chronic fatigue syndrome (CFS) is going to divide opinion. I say that on the basis that graded exercise therapy (GET) as part of a suite of interventions linked into the PACE trial for example, has taken up masses of column inches in the lay and science media over the years and seems set to do so for some time to come.

I'm going to try and talk about the Clark paper as context-free as I can, bearing in mind that science does not exist in some sort of vacuum detached from real-life. I say that on the basis that this is supposed to be a science-related blog and whilst being very much aware of the discussion/politics around the potential rights-and-wrongs of various components of the PACE trial, I don't want them to necessarily spill over to this piece of new science.

So, GETSET - graded exercise therapy guided self-help trial - was the name of trial [2] and the design was such that "an open-label, pragmatic randomised controlled trial done at two UK National Health Service (NHS) secondary-care clinics for chronic fatigue syndrome in central London and Kent" was employed. Over 200 participants diagnosed with CFS - "who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome" - were included for study; half of which were allocated to receive 'specialist medical care' (SMC) with the other half receiving SMC with "additional guided graded exercise self-help (GES)." The trial lasted for 8-12 weeks and the primary outcomes were "fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale)" delivered at baseline and 12 weeks and relying on self-report. We are also told that "Participants were also followed up at 12 months after randomisation, and these results will be published in a separate paper."

Results: as per some further commentary on the study [3] by someone not totally unknown to some of the authors on the Clark paper, the use of SMC + GES did seem to show some effects on self-reported fatigue scores insofar as correlating with "significantly lower mean fatigue score... and higher self-reported physical function score... than did patients managed with specialist medical care alone." They also reported that: "participants in the GES groups had better outcomes than did participants in the control group for work and social adjustment scores, depression, and anxiety, but not for general physical symptoms." Importantly however, it is noted that (a) "physiotherapists reported that 43 participants (42%) adhered to GES completely or very well, 31 (30%) moderately well, and 30 (29%) slightly or not at all" and (b) only about 20% of those receiving GES "noted improvements (“much” or “very much better”) in overall health" and even less (15%) in relation to the symptoms of CFS. This was not a study demonstrating total and universally successful outcomes.

Outside of just those outcomes, the important issue of side-effects or adverse events potentially associated with intervention were also analysed: "non-serious adverse events were reported by 27 (28%) of 97 participants who received guided graded exercise self-help and by 23 (23%) of 102 patients who received specialist medical care only, with no significant differences between the two groups." A couple of participants also dropped out of the study who were using GES but generally intervention seemed to be "well-tolerated" according to the authors.

Limitations? Well, the authors do discuss a few; not least that 'self-report' was the main avenue for data collection. Likewise: "We did not measure any objective outcomes, such as actigraphy, which might have tested the validity of our self-rated measures of physical activity." That last point is quite a large study weakness throughout a lot of research looking at physical activity in many areas, particularly given the availability of some rather accurate and reliable equipment these days (see here). Indeed, the fact that the GES intervention was supervised by physiotherapists yet seemingly had no objective measures of anything physiotherapist-related is a little unusual. I might also add that whilst fatigue is a primary symptom of CFS, there are various other symptom manifestations (e.g. post-exertional malaise, PEM) that also require a lot more investigation in terms of effects from intervention; something particularly pertinent to any intervention that has an 'exertional' component to it. It's also important to note something else discussed by authors: "this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors." Perhaps something of an olive branch is meant by that statement, particularly in light of the issues noted with something like the biopsychosocial (BPS) model being [deleteriously] applied to CFS down the years (see here).

There is a need for further research in this area before anyone gets ahead of themselves with the Clark results as some media headlines seem to have. Other studies [4] combined with opinion from some patient organisations (see here) have highlighted potential issues following the use of GET, and in particular it's use as a 'blanket form of treatment' for CFS. Indeed, 'blanket forms of treatment' have in my mind, been a source of real pain and discomfort to many people suffering (yes, suffering) with CFS; something hopefully being addressed by other research talking about subgroups and phenotypes (see here) and expected changes to clinical guidance here in Blighty for example due quite soon.

As to the question of mechanism(s) pertinent to GET being applied to 'some' CFS, we're still left wanting. I could speculate about issues such as 'de-conditioning' that is bound to be part-and-parcel of CFS and how GET could be targeting this variable. But really, nobody knows everything there is to know about how something like GET might impact on physiology because no-one seems to have measured it in any great detail. Again, quite a few of the trials from the group(s) behind GETSET and PACE have tended to be quite 'light' on physiological measurements before and after intervention; something that perhaps needs to be addressed.

So, there you have it. Some potentially important results but also an area that requires any awful lot more study before any sweeping generalisations are made and made without patient involvement. I await also the follow-up results from this research team to see what happened in the longer term...


[1] Clark LV. et al. Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. Lancet. 2017. June 22.

[2] Clark LV. et al. Graded Exercise Therapy Guided Self-Help Trial for Patients with Chronic Fatigue Syndrome (GETSET): Protocol for a Randomized Controlled Trial and Interview Study. JMIR Res Protoc. 2016 Jun 8;5(2):e70.

[3] Clauw DJ. Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. Lancet. 2017. June 22.

[4] Núñez M. et al. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9.


Tuesday, 27 June 2017

MoBa does prenatal fever and autism risk

'MoBa does..' is fast becoming a common title on this blog (see here and see here). Referring to the Norwegian Mother and Child Cohort Study (MoBa), this initiative based on the examination of 100,000 pregnancies in Norway is yielding some useful observations for all-manner of different condition/labels.

When MoBa is applied to autism, a few names seem to quite consistently crop up - Mady Hornig and Ian 'virus hunter' Lipkin - as is the same for today's blogging material from Hornig and colleagues [1] (open-access). Their findings supporting "a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD [autism spectrum disorder]" make for interesting reading.

Authors set about determining whether maternal fever episodes during pregnancy might show some connection with risk of offspring autism. To do this they relied on questionnaire data from pregnant mums completed at specific times of their pregnancy pertinent to "fever, along with their timing, as well as the names of medications used for fever, and the timing of that medication use" as a function of a subsequent diagnosis of offspring autism or not. That 'medication use' side of things adds to a further stream of research suggesting that some medicines used as fever-reducers/eliminators (antipyretics) during pregnancy might also have some bearing on offspring behavioural/developmental outcomes (see here and see here for examples). Alongside such information, authors also took into account various potentially confounding variables that might have also affected offspring autism risk.

Results: based on data covering nearly 100,000 children, with nearly 600 subsequently being diagnosed with an ASD, researchers concluded that: "Prenatal fever was associated with increased ASD risk among offspring." Exposure to reported pregnancy fever at any time during pregnancy seemed to be more common in those children who were eventually diagnosed with ASD but notably during the second trimester of pregnancy. They also noted a possible dose-response effect from pregnancy fever exposure: "Risks increased markedly and dose dependently with fever frequency, with particularly strong effects after 12 weeks’ gestation." As to the use of antipyretics and any additional risk or mitigation of risk, I'm inclined to suggest that on this research occasion, there wasn't very much to see either way.

Added to the idea that infection exposure during the nine months that makes us might also affect the risk of subsequent offspring autism (see here), this latest data sit well with the idea that infection and/or response to infection during pregnancy might very well be able to influence offspring outcomes. Pregnancy is a time of reprogrammed maternal immune function (to stop mum's immune system attacking the developing foetus) so already science has a basis for looking at something like enhanced maternal immune activation (MIA) during pregnancy as being potentially pertinent to offspring outcomes particularly autism.

Of course one has to note that the strengths of the MoBa study - "a large, prospective, population-based birth cohort with exposure data collected in 4-week intervals and linkage to a patient registry for case ascertainment" - need to be balanced against the weakness, i.e. maternal self-report. The authors have however promised more detailed study in this area: "we are testing the possibility that risk is associated with specific infectious agents through sequence-based and serological assays of samples collected mid-pregnancy and at birth from cases and controls" so there may be more to add in future times [2] in addition to some already published inklings from authors (see here).


[1] Hornig M. et al. Prenatal fever and autism risk. Molecular Psychiatry. 2017. June 13.

[2] Mahic M. et al. Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. mSphere. 2017. June 21.


Monday, 26 June 2017

Ariel pesticide use and neurodevelopmental diagnoses patterns

"When compared with surrounding areas, the zip codes exposed to yearly aerial pyrethroid spraying had a higher prevalence of ASD/DD [autism spectrum disorder/childhood developmental delay]."

One does has to be a little careful in interpreting the results published by Steven Hicks and colleagues [1] (open-access available here) looking at "ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito-borne encephalitis" compared with control areas with "no state-approved aerial applications." Correlation after all, is not the same as causation. But I found the data from Hicks et al to be rather interesting and worthy of a blog entry in light of other, independent peer-reviewed data (see here).

So, looking at all children who were evaluated over a 5-year period at "one of six pediatric outpatient clinics" in New York state, researchers divided participants up depending on their zip code "into aerial-exposed and control zip codes" when it came to pyrethroid spraying. Said spraying was in relation to use of an insecticide "as a preventive tool against mosquitoes carrying eastern equine encephalitis (EEE) and West Nile virus (WNV)." The authors noted that: "The effects of this application on neurodevelopmental patterns in local children have not been investigated."

Pesticide exposure was estimated based on the amount used over a 3-year period in each zip code and reported as kilograms per square kilometre. Alongside looking at rates of "neurodevelopmental delay (ASD and DD)" as a function of zip code/exposure patterns, researchers also included various potentially modifying factors in their calculations: "regional characteristics (poverty, pesticide use, population density, and distance to medical center), subject characteristics (race and sex), and local birth characteristics (prematurity, low birthweight, and birth rates)."

When all was said and done, authors observed a significant relationship between ASD/DD and aerial pesticide exposure. They noted that: "Zip codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD."

Authors caution that "this study is observational and does not establish a causal relationship between pyrethroid exposure and ASD/DD" but also note that there needs to be a lot more experimental study done on how aerial spraying is conducted and any possible effects on the population down below. And before you say anything, yes, I know that aerial spraying is being done for a perfectly valid reason. But that's not to say it should be just given a free pass in terms of either effectiveness or safety...


[1] Hicks SD. et al. Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application. Front Pediatr. 2017 May 24;5:116.


Saturday, 24 June 2017

Autism awareness among the young is actually quite good

The message of 'increasing awareness of autism' is still a strong one in modern times despite the label of autism officially entering medical texts some 80+ years ago. We have a World Autism Awareness Week and a World Autism Awareness Day and lots more in-between to raise awareness of autism and what the label [differentially] means to many, many people.

The findings reported by Karola Dillenburger and colleagues [1] seem to suggest that, particularly among children and young adults, the autism awareness message is getting through as they observed: "Children and young people have good levels of awareness and knowledge about autism and reported positive attitudes towards peers with autism." Even further: "A higher than expected number of children and young people self-reported being on the autism spectrum."

Based on analysis of "two large-scale surveys: the Kids Life and Times survey for 11-year olds and the Young Life and Times survey for 16-year olds" yielding some 3300 children and young adults, researchers posed various questions including those pertinent to autism awareness. The results suggested that some 80% of teenagers had some knowledge about autism compared with about 50% of younger children. Most participants held positive attitudes towards autism including recognition that bullying is an issue that some on the autism spectrum are particularly at risk of. Further: "Self-reported prevalence of autism was 3.1% for teenagers and 2.7% for the younger children." That last point was based on the study population being based in Northern Ireland (which interestingly, has recently reported a rather large upswing in the number of formally-diagnosed cases of autism too).

These are rather positive results insofar as the recognition of autism and indeed, how common it is in modern times. It is perhaps not unexpected that some of these authors have some research form in this area [2]. The authors frame the result in terms of boding well for "peer-mediated support strategies for inclusive education" but I think they go much further than that. Assuming that awareness covers the entire spectrum of autism (see here) and not just a part/branch of it, I'd like to think these findings go some way to supporting efforts to 'make autism more visible' and onward, ensuring that the wants and needs of those on the spectrum are more readily expressed and addressed. Media and culture probably has a lot to do with such findings (see here for example) but the fact that many classrooms and schools do now cater for students on the autism spectrum no doubt played an important role in these findings.


[1] Dillenburger K. et al. Autism awareness in children and young people: surveys of two populations. J Intellect Disabil Res. 2017 Jun 7.

[2] Dillenburger K. et al. Creating an Inclusive Society… How Close are We in Relation to Autism Spectrum Disorder? A General Population Survey. J Appl Res Intellect Disabil. 2015 Jul;28(4):330-40.


Friday, 23 June 2017

How helpful is a 'geek index'?

A quote to begin: "male offspring of older fathers had higher ‘geek index’ scores, a composite measure of high IQ, strong focus on the subject of interest and social aloofness."

So said the findings published by Magdelena Janecka and colleagues [1] (open-access) who set out to determine whether "having an older father is associated with certain beneficial traits" in offspring. Their use of the term 'geek index' (GI) was derived from a "composite measure of non-verbal intelligence, restrictive interests and reduced need to fit in with the peer group" based on data derived from the TEDS (Twin Early Development Study) initiative (something that has cropped up before on this blog). As one might imagine, use of the term 'geek index' in a science article was always likely to make some media headlines (see here for example).

In terms of study design and numbers, this was a biggie with study participants in the thousands. The geek index was derived from scores "of (i) non-verbal intelligence, (ii) restrictive and repetitive behaviours (RRBs) and (iii) social aloofness." Further: "Scores on the Raven’s Standard Progressive Matrices test were used to obtain (i). Childhood Autism Spectrum Test (CAST) scores were used to obtain both (ii) and (iii)." Various statistical 'transformations' were conducted on said scores to give that geek index sum and, not forgetting the parental age bit, paternal age was also thrown into the statistical mix.

As per the opening sentence, those children born to older fathers (but not older mothers) seemed to more frequently present with a higher geek index. This association persisted after controlling for various potentially confounding variables: "maternal age, sex, zygosity and SES [socio-economic status]." Researchers further observed that: "GI was positively linked with future academic attainment—including the key predictors of future SES—suggesting a phenotypic advantage in the offspring of older fathers."

These are interesting results and notwithstanding some study limitations i.e. "It was not possible to determine whether the advantageous effects of GI extend beyond secondary education, and correlate with future SES" require further independent investigation. Offspring being born to older fathers has generally been associated with various less-than-positive outcomes so this article kinda paints a more positive picture for children and families. Indeed, one of the commentators talking about these findings suggests that "perhaps we are destined for future society of geniuses that are going to help us solve all the world's problems." One would hope so.

As per the title of this post, I would however question how useful/helpful the term 'geek index' is when it comes to outcomes and implications. Yes, I know there is such a thing as 'geek chic' these days, but let's not forget that the word 'geek' has it's primary origins as a term of ridicule in many languages. To quote one definition: "the word typically connotes an expert or enthusiast or a person obsessed with a hobby or intellectual pursuit, with a general pejorative meaning of a "peculiar person, especially one who is perceived to be overly intellectual, unfashionable, or socially awkward."" I'm not so sure that every child (youngster or teenager) would be particularly happy to be labelled as scoring high on a geek index. Surely something a little more scientific could replace such a term?

Going also back to those study caveats provided by the authors, I might also raise the idea that just because someone shows an intellectual advantage when it comes to something like STEM (science, technology, engineering and mathematics) subjects does not necessarily mean that their future is going to be a rosy one in terms of employment, income or other markers of SES. “If you look at who does well in life right now, it’s geeks” is one of the quotes attributed to the first author of the paper; and with it as massive a sweeping generalisation as you will ever see.

If we for example, assume that strengths in STEM might be over-represented when it comes to the autism spectrum (see here) we should be seeing lots and lots of people either diagnosed with autism or possessing significant autistic traits thriving in such roles and in life in general. The reality however is that skills pertinent to STEM often do not appear in a vacuum (see here) as I would put forward the suggestion that future research might also consider the possibility of a relationship between the geek index (or other term) and the presentation of something like anxiety or depression and how that might also impact on later adult outcomes for example. The additional idea that social aloofness also makes up part of the geek index is something else that needs quite a lot more work on as part of any 'advantage' arguments being put forward...


[1] Janecka M. et al. Advantageous developmental outcomes of advancing paternal age. Translational Psychiatry. 2017. 7; e1156.


Thursday, 22 June 2017

Autism, learning disability and diagnostic substitution

The findings reported by Cynthia Nevison and Mark Blaxhill [1] represent the source blogging material today. Their quite detailed analysis of individual state data based on the "United States Individuals with Disabilities Education Act" (IDEA) is front and centre and what it might mean for the argument that the quite phenomenal rise in diagnoses of autism or autism spectrum disorder (ASD) is due wholly or in part, to a switch from the diagnosis of intellectual (learning) disability to autism.

Based on examining IDEA data for each of the 50 states of the United States covering various years, various years of birth and various ages, authors concluded that sweeping generalisations about widespread diagnostic switching/substitution were not necessarily borne out in such State level data analysis. They did find that: "Nationwide ID [intellectual disability] prevalence declined steeply over the last two decades, but the decline was driven mainly by ~15 states accounting for only one-fourth of the U.S. school population." Further, when assigning specific statistical conditions to states based on things like the decrease in ID being comparable to the increase in autism diagnoses or the increase in autism diagnoses being substantially greater than the decrease in ID diagnoses, authors reported a complex picture generally pertinent to the idea that "ID prevalence stayed relatively constant while ASD prevalence rose sharply."

This is not the first time that some of these authors have used IDEA data to put forward a view that the increase in cases of autism is real and not just an artifact of changing diagnostic criteria for example (see here). Indeed, both authors have an interest in this area [2] and dedicated some peer-reviewed science time to it. Personally, I find this kind of detailed scrutiny to be refreshing in these days of sweeping generalisations and soundbites about many facets of autism. Indeed, as time goes on and the numbers of those being diagnosed with autism creep ever higher worldwide (see here), older arguments about diagnostic substitution have seemingly become less and less convincing. No, diagnosticians weren't that bad at diagnosing autism X number of years ago...

Having said that, I do still think there is a place for diagnostic substitution when it comes to explaining *some* of the increase in cases being diagnosed. Data such as that from King & Bearman [3] estimating that about a quarter of the increase in cases of autism in places such as California might be due to diagnostic switching from ID cannot simply be forgotten or brushed under the scientific carpet. I should also mention that autism can very well exist in the presence of ID too (see here); even more so in specific populations (see here).

I know that old battle lines about a real vs. artificial increase in cases of autism still persist in many circles and I understand some of the reasons why each side believe what they believe. What is however not in dispute, is the fact that there are quite massive numbers of people (children and adults) being diagnosed as on the autism spectrum year-on-year worldwide (with additional many unable to access timely and appropriate diagnostic services) and resources aplenty are required to identify their specific needs and provide accordingly. No easy task in these continuing days of austerity, cuts and the like...


[1] Nevison CD. & Blaxill M. Diagnostic Substitution for Intellectual Disability: A Flawed Explanation for the Rise in Autism. J Autism Dev Disord. 2017 Jun 6.

[2] Blaxill MF. What's going on? The question of time trends in autism. Public Health Rep. 2004 Nov-Dec;119(6):536-51.

[3] King M. & Bearman P. Diagnostic change and the increased prevalence of autism. Int J Epidemiol. 2009 Oct;38(5):1224-34.


Wednesday, 21 June 2017

Schizophrenia and CRP meta-analysed again

"Our study provides evidence that higher CRP [C-reactive protein] levels are associated with increased risk of SZ [schizophrenia], especially for young adult patients less than 30 years."

So said the results of the 'updated' meta-analysis by Zhichao Wang and colleagues [1] (open-access available here) surveying the peer-reviewed literature on this topic "from inception to November 1, 2016." The 'updated' bit to their discussion refers to the fact that this is not the first time that CRP - a molecule associated with inflammation or inflammatory processes - and schizophrenia have received the meta-analysis treatment (see here for example).

So, "18 studies representing 1963 patients with SZ and 3683 non-SZ controls" were identified and as per the opening sentence to this post, "blood CRP levels were moderately increased in people with SZ... irrespective of study region, sample size of included studies, patient mean age, age of SZ onset and patient body mass index."

The authors do mention the idea that elevated levels of CRP in cases of schizophrenia fits in with the idea that immune function might be doing so much more than just fighting off infection and the like (see here). Indeed, they talk about: "The rationale that plasma CRP levels were increased significantly in studies with participants’age less than 30 years probably lies in that in the early stages of SZ, a particularly large number of inflammatory substances will be secreted, such as blood CRP and interleukin-10, which are very likely to be related to the development of SZ" with the requirement for further investigations. They also talk about how "high peripheral levels of CRP could increase the permeability of the blood–brain barrier through the adjustment of the function of tight junctions, which contributed to the increase in some pro-inflammatory cytokines, such as CRP to enter the central nervous system." This is an idea that has found favour in other quarters too [2].

Armed with such data, one might envisage that further studies on the possibility of controlling CRP and other related compounds (see here) *could* represent one route to eventually treating at least some types of schizophrenia...


[1] Wang Z. et al. Association between C-reactive protein and risk of schizophrenia: An updated meta-analysis. Oncotarget. 2017 May 18.

[2] Najjar S. et al. Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Front Psychiatry. 2017 May 23;8:83.