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Original Investigation
October 7, 2019

Developmental Trajectories of Infants With Multiplex Family Risk for Autism: A Baby Siblings Research Consortium Study

Author Affiliations
  • 1Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles
  • 2Department of Biostatistics, University of California, Los Angeles, Los Angeles
  • 3now with Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco
  • 4Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, Ontario, Canada
  • 5Department of Psychology, University of California, San Diego, La Jolla
  • 6Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
  • 7Child Study Center, Yale University School of Medicine, New Haven, Connecticut
  • 8Department of Psychology, University of Calgary, Calgary, Alberta, Canada
  • 9MIND Institute, Department of Public Health Sciences, University of California, Davis, Davis
  • 10Centre for Brain & Cognitive Development, Birkbeck, University of London, London, United Kingdom
  • 11Marcus Autism Center, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia
  • 12Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Maryland
  • 13Department of Psychology, University of Miami, Coral Gables, Florida
  • 14Department of Pediatrics, University of Miami, Coral Gables, Florida
  • 15Department of Electrical & Computer Engineering, University of Miami, Coral Gables, Florida
  • 16Department of Music Engineering, University of Miami, Coral Gables, Florida
  • 17MIND Institute, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento
  • 18Department of Psychology, University of Washington, Seattle
  • 19Department of Psychology & Brain Sciences, Boston University, Boston, Massachusetts
  • 20Psychiatry and Behavioral Sciences, University of Washington, Seattle
  • 21Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
  • 22Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada
JAMA Neurol. Published online October 7, 2019. doi:10.1001/jamaneurol.2019.3341
Key Points

Question  How does the development of infants with multiplex and single-incidence family risk for autism spectrum disorder (ASD) differ?

Findings  In this longitudinal cohort study of 445 children with multiplex or single-incidence family risk, 68% of children from multiplex families vs 43% of those from single-incidence families had ASD or atypical development at outcome. Children without ASD did not differ in ASD symptoms based on family risk status, but multiplex status was associated with lower cognitive abilities by age 3 years.

Meaning  Infants with a multiplex family history of ASD should be monitored early and often and referred for early intervention services at the first sign of concern.


Importance  Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different genetic etiologies. Prospective examination of familial-risk infants informs understanding of developmental trajectories preceding ASD diagnosis, potentially improving early detection.

Objective  To compare outcomes and trajectories associated with varying familial risk for ASD across the first 3 years of life.

Design, Setting, and Participants  This longitudinal, prospective cohort study used data from 11 sites in the Baby Siblings Research Consortium database. Data were collected between 2003 and 2015. Infants who were younger siblings of children with ASD were followed up for 3 years. Analyses were conducted in April 2018. Of the initial 1008 infants from the database, 573 were removed owing to missing necessary data, diagnostic discrepancies, or only having 1 older sibling.

Exposures  Number of siblings with ASD.

Main Outcomes and Measures  Outcomes included ASD symptoms, cognitive abilities, and adaptive skills. Diagnosis (ASD or no ASD) was given at 36-month outcome. The no-ASD group was classified as atypical (developmental delays and/or social-communication concerns) or typical for some analyses. Generalized linear mixed models examined developmental trajectories by ASD outcome and familial-risk group.

Results  In the 435 analyzed participants (age range at outcome, 32-43 months; 246 male [57%]), 355 (82%) were from single-incidence families (1 sibling with ASD and ≥1 sibling without ASD) and 80 (18%) were from multiplex families (≥2 siblings with ASD). There were no significant group differences in major demographics. Children from multiplex families were more likely than those from single-incidence families to be classified as having ASD (29 of 80 [36%] vs 57 of 355 [16%]; 95% CI, 9%-31%; P < .001) and less likely as typical (26 of 80 [33%] vs 201 of 355 [57%]; 95% CI, −36% to −13%; P < .001), with similar rates of atypical classifications (25 of 80 [31%] vs 97 of 355 [27%]; 95% CI, −7% to 15%; P = .49). There were no differences in ASD symptoms between multiplex and single-incidence groups after controlling for ASD outcome (95% CI, −0.02 to 0.20; P = .18). During infancy, differences in cognitive and adaptive abilities were observed based on ASD outcome in the single-incidence group only. At 36 months, the multiplex/no-ASD group had lower cognitive abilities than the single-incidence/no-ASD group (95% CI, −11.89 to −2.20; P = .02), and the multiplex group had lower adaptive abilities than individuals in the single-incidence group after controlling for ASD outcome (95% CI, −9.01 to −1.48; P = .02).

Conclusions and Relevance  Infants with a multiplex family history of ASD should be monitored early and often and referred for early intervention at the first sign of concern. Direct examination of genetic contributions to neurodevelopmental phenotypes in infants with familial risk for ASD is needed.

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