Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis.

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Document Type: Report
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Keywords: Autism spectrum disorder; neurodevelopment; infancy; pupillary light reflex Background Although autism spectrum disorder (ASD) is heritable, the mechanisms through which genes contribute to symptom emergence remain unclear. Investigating candidate intermediate phenotypes such as the pupillary light reflex (PLR) prospectively from early in development could bridge genotype and behavioural phenotype. Methods Using eye tracking, we longitudinally measured the PLR at 9, 14 and 24 months in a sample of infants (N = 264) enriched for a family history of ASD; 27 infants received an ASD diagnosis at 3 years. We examined the 9- to 24-month developmental trajectories of PLR constriction latency (onset; ms) and amplitude (%) and explored their relation to categorical 3-year ASD outcome, polygenic liability for ASD and dimensional 3-year social affect (SA) and repetitive/restrictive behaviour (RRB) traits. Polygenic scores for ASD (PGS.sub.ASD) were calculated for 190 infants. Results While infants showed a decrease in latency between 9 and 14 months, higher PGS.sub.ASD was associated with a smaller decrease in latency in the first year ([beta] = -.16, 95% CI = -0.31, -0.002); infants with later ASD showed a significantly steeper decrease in latency (a putative 'catch-up') between 14 and 24 months relative to those with other outcomes (typical: [beta] = .54, 95% CI = 0.08, 0.99; other: [beta] = .53, 95% CI = 0.02, 1.04). Latency development did not associate with later dimensional variation in ASD-related traits. In contrast, change in amplitude was not related to categorical ASD or genetics, but decreasing 9- to 14-month amplitude was associated with higher SA ([beta] = .08, 95% CI = 0.01, 0.14) and RRB ([beta] = .05, 95% CI = 0.004, 0.11) traits. Conclusions These findings corroborate PLR development as possible intermediate phenotypes being linked to both genetic liability and phenotypic outcomes. Future work should incorporate alternative measures (e.g. functionally informed structural and genetic measures) to test whether distinct neural mechanisms underpin PLR alterations. Article Note: Conflict of interest statement: No conflicts declared. CAPTION(S): Appendix S1. PLR stimuli and processing. Appendix S2. 3-year Clinical outcome. Appendix S3. DNA Processes and Polygenic Score Calculations. Appendix S4. Sample characteristics. Appendix S5. Model results. Appendix S6. Overview of findings. Table S1. Mean number of trials included and percentage of trials missing during processing for each PLR parameter for each visit. Table S2. 3-year sample characteristics of individuals with PLR from at least one timepoint from 9 to 24 months. Table S3. Results from ANOVA and Tukey pairwise comparisons examining group-wise differences in age across outcome at each timepoint. Table S4. Results from ANOVA and Tukey pairwise comparisons examining group-wise differences in M-ELC across outcome at each timepoint. Table S5. Sample size and characteristics describing, age, Mullen Early Learning Composite score (M-ELC) across 3-year outcome group for each visit timepoint for individuals with PLR Amplitude data. Table S6. Standardised and unstandardised fixed effect estimates for association between outcome and PLR Amplitude obtained using linear mixed effect models. Table S7. Standardised and unstandardised random Effect variance and standard deviation for association between outcome and PLR Amplitude obtained using linear mixed effect models. Table S8. Estimated marginal means obtained using LMM on the relation between PLR Amplitude and 3-year ASD outcome over visits. Table S9. Standardised and unstandardised fixed effect estimates for association between outcome and PLR Amplitude obtained using linear mixed effect models including mean distance from screen as covariate. Table S10. Standardised and unstandardised fixed effect estimates for association between outcome and PLR Latency obtained using linear mixed effect models. Table S11. Standardised and unstandardised random Effect variance and standard deviation for association between outcome and PLR Latency obtained using linear mixed effect models. Table S12. Estimated marginal means obtained using LMM on the relation between PLR Latency (ms) and 3-year ASD outcome over visits. Table S13. Standardised and unstandardised pairwise comparisons of Latency within outcome group across 14 to 24 months. Table S14. Standardised and unstandardised fixed effect estimates for association between outcome and PLR Latency obtained using linear mixed effect models including mean distance from screen as covariate. Table S15. Standardised and unstandardised fixed effect estimates for association between ASD polygenic score and PLR Amplitude obtained using linear mixed effect models. Table S16. Standardised and unstandardised random effect variance and standard deviation for association between ASD polygenic score and PLR Amplitude obtained using linear mixed effect models. Table S17. Standardised and unstandardised fixed effect estimates for association between ASD polygenic score and PLR Amplitude obtained using linear mixed effect models including mean distance from screen as covariate. Table S18. Standardised and unstandardised fixed effect estimates for association between ASD polygenic score and PLR Latency obtained using linear mixed effect models. Table S19. Standardised and unstandardised random Effect variance and standard deviation for association between ASD polygenic score and PLR Latency obtained using linear mixed effect models. Table S20. Standardised and unstandardised fixed effect estimates for association between ASD polygenic score and PLR Latency obtained using linear mixed effect model models including mean distance from screen as covariate. Table S21. Standardised and unstandardised fixed effect estimates for associations between ADOS-CSS score (social affect or repetitive behaviours) and PLR Amplitude obtained using linear mixed effect models. Table S22. Random Effect variance and standard deviation for associations between ADOS score (social affect or repetitive behaviours) and PLR Amplitude obtained using linear mixed effect models. Table S23. Standardised and unstandardised fixed effect estimates for association between ADOS and PLR Amplitude obtained using linear mixed effect model models including mean distance from screen as covariate. Table S24. Standardised and unstandardised fixed effect estimates for associations between ADOS score (social affect or repetitive behaviours) and PLR Latency obtained using linear mixed effect models. Table S25. Random Effect variance and standard deviation for associations between ADOS score (social affect or repetitive behaviours) and PLR Latency obtained using linear mixed effect models. Table S26. Standardised and unstandardised fixed effect estimates for association between ADOS and PLR Latency obtained using linear mixed effect model models including mean distance from screen as covariate. Table S27. Summary of findings for models on PLR Amplitude. Table S28. Summary of findings for models on PLR Latency. Figure S1. Distribution of individual's remaining trials contributing to the (a) PLR Latency and (b) PLR Amplitude values split by visit. Figure S2. Standardised best-fit PGSASD per 3-year outcome. Byline: Barbara Franke, Eric Fombonne, Angelica Ronald, Laurel A. Fish, Pär Nyström, Teodora Gliga, Anna Gui, Jannath Begum Ali, Luke Mason, Shruti Garg, Jonathan Green, Mark H. Johnson, Tony Charman, Rebecca Harrison, Emma Meaburn, Terje Falck-Ytter, Emily J. H. Jones,

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Gale Document Number: GALE|A680418260