title: 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 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.
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. Electronic address: raznahana@mail.nih.gov.
authors.forename: Armin
authors.initials: A
authors.lastname: Raznahan
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Wallace
authors.forename: Ligia
authors.initials: L
authors.lastname: Antezana
authors.forename: Dede
authors.initials: D
authors.lastname: Greenstein
authors.forename: Rhoshel
authors.initials: R
authors.lastname: Lenroot
authors.forename: Audrey
authors.initials: A
authors.lastname: Thurm
authors.forename: Marta
authors.initials: M
authors.lastname: Gozzi
authors.forename: Sarah
authors.initials: S
authors.lastname: Spence
authors.forename: Alex
authors.initials: A
authors.lastname: Martin
authors.forename: Susan E
authors.initials: SE
authors.lastname: Swedo
authors.forename: Jay N
authors.initials: JN
authors.lastname: Giedd
mesh_terms: D000367:Age Factors; D001321:Autistic Disorder / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002675:Child, Preschool; D006257:Head / Q000473:pathology*; D006801:Humans; D008297:Male; D011153:Population
keywords: Autism; CDC; WHO; bias; head circumference; systematic review