Skewed Norms Weaken Case for Early Brain Overgrowth in Autism

Biases in standardized norms used to compare data on head size weaken evidence for early excess brain growth in autism, say NIMH intramural researchers. Their analysis of existing and new data undermines the case that had been building for such early brain enlargement as a potential biomarker that might be used in making treatment decisions.

"Our results show that the most highly replicated aspects of early brain overgrowth in autism are not a feature of the disease, but instead arise through replicable biases in the population growth norms that have been used to define brain overgrowth in autism".explained Armin Raznahan, M.D., Ph.D.

Raznahan and NIMH Child Psychiatry Branch colleagues reported their findings online May 23, 2013, in the journal Biological Psychiatry.

Background

Although still a hypothesis, dramatic early brain overgrowth during the first year of life had become widely-viewed as a likely hallmark feature of autism, raising hopes that it might find application as a biomarker.

Most studies reporting such early brain overgrowth in autism have been based on head circumference as a proxy for brain size. Researchers have typically compared head circumference of children with autism to – as a control group – standardized charts of head circumference published by the Center for Disease Control (CDC), and World Health Organization (WHO).

Ten of 11 long-term studies of head circumference in autism had been published since the last time the topic had been systematically reviewed. Also, discrepancies had emerged between the norms used in autism studies and recent patterns of head growth emerging from several more recent large non-autism studies. Typically-developing young children’s heads seemed to be growing faster, so that they looked strikingly similar to the overgrowth – it turns out perhaps erroneously – ascribed to autism. This suggested that previous studies had been based on norms that underestimated typical early brain growth.

Suspecting that the norms might be skewed by various sources of bias, the NIMH researchers reexamined them in light of the updated data from 34 relevant studies. They integrated crosssectional and longitudinal head circumference data between birth and 18 months. They also included 330 head circumference measures from their own longitudinal study that followed 35 children with autism and 22 typically developing controls as they grew up, from birth to 18 years old.

Results of This study

"The most methodologically robust and bias-free sources of evidence are equivocal regarding the presence of abnormally accelerated early brain growth in autism" said Raznahan.

In the few studies that did find evidence of such early brain overgrowth, head circumference in children with autism showed a "subtle divergence" from that in controls during the second year of life, rather than in the first year.

Significance

Earlier studies overestimated early brain growth in children with autism because their head circumference data was compared to published norms that were wrong – based on studies that underestimated typical head circumference/brain growth.

Inconsistencies that turned up in the study suggest the possibility of a more subtle, lateremerging pattern of early brain overgrowth among only a subgroup of children with autism. Since some related disorders show brain undergrowth, the results are also consistent with the idea that extreme dysregulation of brain growth – as opposed to brain enlargement per se – may be more relevant to understanding autism spectrum disorders.

What's Next

Use of head circumference as an index of brain size offers practical advantages over more sophisticated measures, such as structural magnetic resonance imaging, in longitudinal studies, provided that the methodological pitfalls can be minimized, say the researchers.

Future studies might compare evidence for extreme versus isolated overgrowth and possible links between aberrant brain size and genetic and environmental influences prior to, or just after, birth, they add.

"These findings have far-reaching implications for use of standardized growth norms extending well beyond autism to decision-making across medicine." said Raznahan, who suggests that widely-used norms be reevaluated in light of the new evidence.

Reference

Compared to What? Early Brain Overgrowth in Autism and the Perils of Population Norms.  Raznahan A, Wallace GL, Antezana L, Greenstein D, Lenroot R, Thurm A, Gozzi M, Spence S, Martin A, Swedo SE, Giedd JN. Biol Psychiatry. 2013 May 23. doi:pii: S0006-3223(13)00303- X. 10.1016/j.biopsych.2013.03.022. [Epub ahead of print] PMID:23706681