Compared to What? Early Brain Overgrowth in Autism and the Perils of Population Norms

Abstract

Background Early brain overgrowth (EBO) in autism spectrum disorder (ASD) is amongst the best-replicated biological associations in psychiatry. Most positive reports have compared head circumference (HC) in ASD (an excellent proxy for early brain size) with well-known reference norms. We sought to reappraise evidence for the EBO hypothesis given (i) the recent proliferation of longitudinal HC studies in ASD, and (ii) emerging reports that several of the reference norms used to define EBO in ASD may be biased towards detecting HC overgrowth in contemporary samples of healthy children. Methods (1)Systematic review of all published HC studies in children with ASD. (2)Comparison of 330 longitudinally gathered HC measures between birth and 18 months from male children with autism(n=35) and typically developing controls(n=22). Results In systematic review, comparisons with locally recruited controls were significantly less likely to identify EBO in ASD than norm-based studies(p<0.006). Through systematic review and analysis of new data we replicate seminal reports of EBO in ASD relative to classical HC norms, but show that this overgrowth relative to norms is mimicked by patterns of HC growth age in a large contemporary community-based sample of US children(n~75,000). Controlling for known HC norm biases leaves inconsistent support for a subtle, later-emerging and sub-group specific pattern of EBO in clinically-ascertained ASD vs. community controls. Conclusions The best-replicated aspects of EBO reflect generalizable HC norm biases rather than disease-specific biomarkers. The potential HC norm biases we detail are not specific to ASD research, but apply throughout clinical and academic medicine.

Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan

“…For example, in 2013, Raznahan and colleagues 29 suggested that the well-replicated fi nding of a signifi cant increase in head circumference in ASD-which accompanies the increase in total brain volume-might in fact be a result of a bias in population norms rather than a replicable pattern of dysregulated growth. 29 Future investigations into population norms will also be important when considering the large phenotypic diversity of the brain in ASD, which can only be reliably interpreted in the context of the wide neuroanatomical diversity within the general population. 30 Evidence also suggests that early brain overgrowth in ASD is not restricted to the brain exclusively, but that early generalised patterns of physical (ie, somatic) overgrowth occur in ASD, particularly in boys.…”

Early Identification of Autism Spectrum Disorder: Recommendations for Practice and Research

“…87 Head circumference, which is a crude proxy for brain size, is generally consistent with brain enlargement in ASD, 84 although a recent review has raised questions as to whether ASD-related increases in head circumference have been largely driven by comparison with outdated population-based norms. 92 As such, MRI is the gold standard for indexing structural brain development in ASD.…”

ASD Validity

“…Counter to the early brain overgrowth model, though, Chaste et al (2013), Raznahan et al (2013), and Cederlund et al (2014) all concluded that very few children with ASD had early brain overgrowth, and Raznahan et al (2013) reported that larger ASD head circumference was not found when local TD controls were used. Lainhart (2015) reviewed research and noted that only Ba very small subgroup of ASD children^(p. 79) had larger brain volumes.…”