Nicole M McDonald1, Damla Senturk2, Aaron Scheffler2,3, Jessica A Brian4, Leslie J Carver5, Tony Charman6, Katarzyna Chawarska7, Suzanne Curtin8, Irva Hertz-Piccioto9, Emily J H Jones10, Ami Klin11, Rebecca Landa12, Daniel S Messinger13,14,15,16, Sally Ozonoff17, Wendy L Stone18, Helen Tager-Flusberg19, Sara Jane Webb20, Gregory Young17, Lonnie Zwaigenbaum21,22, Shafali S Jeste1. 1. Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles. 2. Department of Biostatistics, University of California, Los Angeles, Los Angeles. 3. now with Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco. 4. Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, Ontario, Canada. 5. Department of Psychology, University of California, San Diego, La Jolla. 6. Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. 7. Child Study Center, Yale University School of Medicine, New Haven, Connecticut. 8. Department of Psychology, University of Calgary, Calgary, Alberta, Canada. 9. MIND Institute, Department of Public Health Sciences, University of California, Davis, Davis. 10. Centre for Brain & Cognitive Development, Birkbeck, University of London, London, United Kingdom. 11. Marcus Autism Center, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia. 12. Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Maryland. 13. Department of Psychology, University of Miami, Coral Gables, Florida. 14. Department of Pediatrics, University of Miami, Coral Gables, Florida. 15. Department of Electrical & Computer Engineering, University of Miami, Coral Gables, Florida. 16. Department of Music Engineering, University of Miami, Coral Gables, Florida. 17. MIND Institute, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento. 18. Department of Psychology, University of Washington, Seattle. 19. Department of Psychology & Brain Sciences, Boston University, Boston, Massachusetts. 20. Psychiatry and Behavioral Sciences, University of Washington, Seattle. 21. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. 22. Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
Abstract
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.
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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