Elsevier

Biological Psychiatry

Volume 74, Issue 8, 15 October 2013, Pages 563-575
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2013.03.022Get rights and content

Background

Early brain overgrowth (EBO) in autism spectrum disorder (ASD) is among 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 1) the recent proliferation of longitudinal HC studies in ASD, and 2) emerging reports that several of the reference norms used to define EBO in ASD may be biased toward detecting HC overgrowth in contemporary samples of healthy children.

Methods

Systematic review of all published HC studies in children with ASD. Comparison of 330 longitudinally gathered HC measures between birth and 18 months from male children with autism (n = 35) and typically developing control subjects (n = 22).

Results

In systematic review, comparisons with locally recruited control subjects were significantly less likely to identify EBO in ASD than norm-based studies (p < .001). 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 subgroup specific pattern of EBO in clinically ascertained ASD versus community control subjects.

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.

Section snippets

Systematic Review

Three authors (A.R., G.L.W., L.A.) independently carried out an electronic literature search (PubMed [National Library of Medicine, Bethesda, Maryland], EMBASE [Elsevier, Amsterdam, The Netherlands]; start of records until June 30, 2012) and manual bibliography search to identify all available studies of HC in children with ASD. Electronic literature search terms included: AUT*, ASPERGER*, ASD, PERVASIVE DEVELOPMENTAL DISORDER, PDD, HEAD CIRCUMFERENCE, OFC, and OVERGROWTH. For a study to enter

Systematic Review

Table 1 lists the 34 studies identified by our systematic review 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 35, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, according to publication date and study characteristics.

Survey of Normative Data Used to Test EBO Hypothesis in ASD. Of the 34 studies identified, 21 studies made exclusive use of HC norms as comparison data when testing the EBO hypothesis, 8 studies used both norms and locally recruited control

Discussion

Our systematic review identifies several lines of evidence that the use of HC population norms has introduced systematic age-dependent biases in studies of early brain growth in ASD. We were able to replicate and better specify the nature of these age-dependent HC norm biases by analyzing a new set of HC data in children with ASD against different sources of control data.

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