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. 2013 Oct 15;74(8):563-75.
doi: 10.1016/j.biopsych.2013.03.022. Epub 2013 May 23.

Compared to what? Early brain overgrowth in autism and the perils of population norms

Armin Raznahan  1 , Gregory L Wallace, Ligia Antezana, Dede Greenstein, Rhoshel Lenroot, Audrey Thurm, Marta Gozzi, Sarah Spence, Alex Martin, Susan E Swedo, Jay N Giedd
Affiliations

Compared to what? Early brain overgrowth in autism and the perils of population norms

Armin Raznahan et al. Biol Psychiatry. .

Abstract

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.

Keywords: Autism; CDC; WHO; bias; head circumference; systematic review.

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Figures

FIGURE 1
FIGURE 1. Systematic Review Findings
1A) Cross-sectional studies (in reverse order of publication year) grouped according to use of HC norms vs. locally recruited controls as a comparison for ASD data: This grouping was significantly associated with study outcome (Chi-squared=7.5, p=0.006). A “negative” study outcome was also associated with a narrower study age-range (t=2.3, p=.03). Each study is a horizontal bar spanning the study age-range, with study outcome coded by color, and density of HC observations coded by bar height. Where one study reported multiple cross-sectional tests the coded outcome relates to analysis of raw HC where available and HC centile where not. Outcomes are coded before any control for body size. 1B) Summary of reported macrocephaly rates in ASD grouped according to use of expected macrocephaly rate in HC norms (3%) or observed macrocephaly rate in controls as a comparison: Each reported rate is a point, with significance of test for macrocephaly enrichment in ASD coded by shape, HC norm is coded by color, and density of HC observations coded by size. Study stratification by comparison group was significantly associated with study outcome (Chi-squared=10.5, p=0.005). 1C) Longitudinal studies grouped according to use of HC norms vs. locally recruited controls as a comparison for ASD data: Each study is a horizontal bar spanning the study age-range, with periods of abnormal HC change in ASD coded by color, and density of HC observations coded by bar height.
FIGURE 1
FIGURE 1. Systematic Review Findings
1A) Cross-sectional studies (in reverse order of publication year) grouped according to use of HC norms vs. locally recruited controls as a comparison for ASD data: This grouping was significantly associated with study outcome (Chi-squared=7.5, p=0.006). A “negative” study outcome was also associated with a narrower study age-range (t=2.3, p=.03). Each study is a horizontal bar spanning the study age-range, with study outcome coded by color, and density of HC observations coded by bar height. Where one study reported multiple cross-sectional tests the coded outcome relates to analysis of raw HC where available and HC centile where not. Outcomes are coded before any control for body size. 1B) Summary of reported macrocephaly rates in ASD grouped according to use of expected macrocephaly rate in HC norms (3%) or observed macrocephaly rate in controls as a comparison: Each reported rate is a point, with significance of test for macrocephaly enrichment in ASD coded by shape, HC norm is coded by color, and density of HC observations coded by size. Study stratification by comparison group was significantly associated with study outcome (Chi-squared=10.5, p=0.005). 1C) Longitudinal studies grouped according to use of HC norms vs. locally recruited controls as a comparison for ASD data: Each study is a horizontal bar spanning the study age-range, with periods of abnormal HC change in ASD coded by color, and density of HC observations coded by bar height.
FIGURE 1
FIGURE 1. Systematic Review Findings
1A) Cross-sectional studies (in reverse order of publication year) grouped according to use of HC norms vs. locally recruited controls as a comparison for ASD data: This grouping was significantly associated with study outcome (Chi-squared=7.5, p=0.006). A “negative” study outcome was also associated with a narrower study age-range (t=2.3, p=.03). Each study is a horizontal bar spanning the study age-range, with study outcome coded by color, and density of HC observations coded by bar height. Where one study reported multiple cross-sectional tests the coded outcome relates to analysis of raw HC where available and HC centile where not. Outcomes are coded before any control for body size. 1B) Summary of reported macrocephaly rates in ASD grouped according to use of expected macrocephaly rate in HC norms (3%) or observed macrocephaly rate in controls as a comparison: Each reported rate is a point, with significance of test for macrocephaly enrichment in ASD coded by shape, HC norm is coded by color, and density of HC observations coded by size. Study stratification by comparison group was significantly associated with study outcome (Chi-squared=10.5, p=0.005). 1C) Longitudinal studies grouped according to use of HC norms vs. locally recruited controls as a comparison for ASD data: Each study is a horizontal bar spanning the study age-range, with periods of abnormal HC change in ASD coded by color, and density of HC observations coded by bar height.
FIGURE 2
FIGURE 2. Reported Patterns of HC Growth Between Birth and 18 Months within the Common Framework of CDC Head Circumference Reference Norms
The trajectory for expected growth according to CDC norms (50th centile) is shown as a horizontal solid black line. The trajectories for expected growth according to PCN norms (50th centile) is shown as dashed black line. 2A) Prior reports in ASD: Each study is a differently colored solid line. 2B) Prior reports for control groups include in studies of HC in ASD: Each study is a differently colored solid line. 2C) Summary of weighted mean ASD (solid red) and control (solid blue) HC trajectories. Confidence intervals are not shown as constituent studies did not uniformly provide estimates of error for reported group HC means.
FIGURE 3
FIGURE 3. Estimates of Mean HC centile (with 95% Confidence Intervals) for ASD and Control Participants at Each Age-point According Different HC Norms
A) CDC, B) WHO and C) PCN HC norms. For HC in both the ASD and control group (i) mean CDC centile rises steeply from birth to reach a plateau at about 8 months, (ii) mean WHO centile is within expected limits at birth, but abnormally elevated thereafter, and (iii) mean PCN centile adheres most closely to the expected “flat” trajectory.
FIGURE 4
FIGURE 4. Growth Curve Modeling of HC Data in New Cohort and Combination of New Cohort Findings With Summaries From Systematic Review
A) Patterns of HC change in new cohort of participants with ASD and controls. Each person is depicted as a set of connected points, with overall group-best fit trajectories shown as bold solid lines: Color-coded for group (ASD-red, controls-blue). B) Group best-fit longitudinal HC trajectories in new cohort and weighted mean HC trajectories generated by systematic review, shown as CDC centile. The trajectories for expected growth (50th centile) according to CDC norms is shown as a horizontal solid black line. The trajectories for expected growth (50th centile) according to PCN norms are shown as dashed black line. C) Group best-fit longitudinal HC trajectories in new cohort and weighted mean HC trajectories generated by systematic review, shown as PCN centile. The trajectories for expected growth (50th centile) according to PCN norms is shown as a horizontal solid black line. Confidence intervals are not shown as constituent studies did not uniformly provide estimates of error for reported group HC means.
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