Deficits in eye contact have been a hallmark of autism 1,2 since the condition's initial description 3 . They are cited widely as a diagnostic feature 4 and figure prominently in clinical instruments 5 ; however, the early onset of these deficits has not been known. Here we show in a prospective longitudinal study that infants later diagnosed with autism spectrum disorders (ASDs) exhibit mean decline in eye fixation from 2 to 6 months of age, a pattern not observed in infants who do not develop ASD. These observations mark the earliest known indicators of social disability in infancy, but also falsify a prior hypothesis: in the first months of life, this basic mechanism of social adaptive action-eye looking-is not immediately diminished in infants later diagnosed with ASD; instead, eye looking appears to begin at normative levels prior to decline. The timing of decline highlights a narrow developmental window and reveals the early derailment of processes that would otherwise have a key role in canalizing typical social development. Finally, the observation of this decline in eye fixation-rather than outright absence-offers a promising opportunity for early intervention that could build on the apparent preservation of mechanisms subserving reflexive initial orientation towards the eyes. Autism Spectrum Disorders (ASDs) affect approximately 1 in every 88 individuals 6 . These disorders are lifelong, believed to be congenital, and are among the most highly heritable of psychiatric conditions 7 . However, the genetic heterogeneity of ASD-with estimates suggesting as many as three-to five-hundred distinct genes impacting aetiology 8poses a stark challenge for understanding the biology of the condition: with so many different 'causes', a key question is how that genetic heterogeneity can be instantiated into common forms of disability. One answer is that although the specific biological mechanisms may vary (in genes or pathways affected, in dosage or in timing), any such disruptions will contribute to an individual deviation from normative developmental processes 9,10 ; the mechanisms may initially be different, but a divergence from typical development is shared. In this way, widely varying initial liabilities can be converted into similar manifestations of impairment, giving rise to the spectrum of social disability we then call 'autism'. In typical development, the processes of normative social interaction are extremely early-emerging: from the first hours and weeks of life, preferential attention to familiar voices 11 , faces 12 , face-like stimuli 13 and biological motion 14 guide typical infants 15 . These processes are highly conserved phylogenetically 16 and lay the foundation for iterative specialization of mind and brain 17 , entraining babies to the social signals of their caregivers [11] [12] [13] [14] 18 . In the current study, we tested the extent to which measures of these early-emerging normative processes may reveal disruptions in ASD at a point prior to the manifestation of overt symptoms. We measured preferential attention to the eyes of others, a skill present in typical infants 12 but significantly impaired in 2-year-olds with ASD 2 . We proposed that in infants later diagnosed with ASD, preferential attention to others' eyes might be diminished from birth onwards 2,3,17 . Data were collected at 10 time points: at months 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24. We studied 110 infants, enrolled as risk-based cohorts: n 5 59 at high-risk for ASD (full siblings of a child with ASD 19 ) and n 5 51 at low-risk (without first-, second-or third-degree relatives with ASD). Diagnostic status was ascertained at 36 months. For details on study design, clinical characterization of participants, and experimental procedures, see Methods and Supplementary Information. Of the high-risk infants, 12 met criteria for ASD 20 (10 males, 2 females), indicating a conversion rate of 20.3% 19 . One child from the low-risk cohort was also diagnosed with ASD. Given the small number of girls in the ASD group, we constrained current analyses to males only, 11 ASD (10 from the high-risk cohort and 1 from the low-risk), and 25 typically developing (all from the low-risk cohort). At each testing session, infants viewed scenes of naturalistic caregiver interaction (Fig. 1a, b ) while their visual scanning was measured with eye-tracking equipment. The 36 typically developing and ASD children viewed 2,384 trials of video scenes. Control comparisons tested for between-group differences in attention to task and completion of procedures. There were no betweengroup differences in duration of data collected per child (typically developing 5 71.25 (27.66) min, ASD 5 64.16 (30.77) min, data given as mean (standard deviation), with t 34 5 0.685, P 5 0.498; two-sample t-test with 34 degrees of freedom, equal variances); or in the distribution of ages at which successful data collection occurred (k 5 0.0759, P 5 0.9556; two-sample Kolmogorov-Smirnov test). Calibration accuracy was not significantly different between groups: either cross-sectionally, at any data collection session (all P . 0.15, t , 1.44; mean P 5 0.428); or longitudinally, as either a main effect of diagnosis (F 1,2968.336 5 0.202, P 5 0.65) or as an interaction of diagnosis by time (F 1,130.551 5 0.027, P 5 0.87) (by hierarchical linear modelling; see Methods, Supplementary Information and Extended Data Fig. 8 ). We then measured percentage of visual fixation time to eyes, mouth, body and object regions (Fig. 1c) . For each child, during each video, these measures served as the dependent variables for longitudinal analyses. Longitudinal analyses were conducted by functional data analysis (FDA) 21 and principal analysis by conditional expectation (PACE) 22 (examples in Fig. 1d, e ), and were repeated with traditional growth curve analysis using hierarchical linear modelling (HLM) 23 .
Likewise, a longitudinal study examined the patterns of eye fixation for infants aged 2 to 6 months REF .
Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism
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Medicine