Several conclusions may be drawn from this study. As expected, many sleep problems were most prevalent in early and middle childhood, suggesting that treatments may need to be tailored toward sleep problems evident in younger children. These included bedtime problems and the need for a parent to lay down with the child, difficulty falling asleep, and frequent/prolonged awakenings. However, children in middle childhood had more difficulty waking than those in early and late childhood, and children in late childhood had more excess daytime sleepiness than younger children, implying that treatments will need to evolve as children age.
Using the SSC sample, this study confirmed numerous prior reports of sleep problems in children with ASD. These reports reinforce the need for health care professionals to screen for and discuss sleep problems with their ASD patients and families. As recommended by Malow et al. (2014), parental education in proper sleep habits should be provided. Use of the SSCSI may be used to screen for sleep problems in children with ASD in primary care and sleep medicine clinics, as well as in a range of specialty clinics—neurology, pulmonology, cardiology, behavioral medicine, etc. This screening may aid in proper diagnosis and treatment of other symptoms, and contribute to holistic, multispecialty care. In addition, as sleep has been associated with behavioral, cognitive, and biological variables, the SSC provides a wealth of opportunities to incorporate sleep into research in this large, well-characterized sample of children with ASD. The SSCSI may be used by such researchers to incorporate sleep patterns into studies focusing on a wide range of variables.
This study advances the understanding of sleep and ASD by showing that presence of GID, seizures, young age, and low NVIQ increase the odds of having sleep problems. As other studies have found, nearly half of children in this sample were reported to have GID, and these gastric symptoms were significantly related to sleep problems. The current study additionally found that rates of GID and its relationship to sleep problems were not different between age groups or sexes. Seizures were found to be significantly associated with composite sleep problems and nighttime problems, but not daytime problems
or sleep duration problems, which may imply that seizure activity impacts length, depth, and/or microarchitecture of sleep patterns. That low NVIQ (more severe symptoms), but not ASD severity, is related to increased composite sleep problems is intriguing and will require more investigation to explain. These results, however, emphasize that practitioners and researchers from many specialties must be attentive for sleep problems in their ASD populations.
The second aim of this study attempted to determine if there are genetic associations between melatonin/SCN genes and sleep patterns using association analysis and transmission disequilibrium tests. Variants were chosen because of their significant effect on expression of target genes, primarily in the brain. However, genetic analysis of the 72 eQTLs and SNPs did not demonstrate association with sleep problems in this sample, indicating that variation in expression, or transcription, of genes in the melatonin/SCN pathway is likely not a driver of sleep problems. If transcription is not driving sleep problems, a number of research questions now follow, including the role of post-translational modification of melatonin/SCN proteins and epigenomic mechanisms in sleep problems, and the contribution of other sleep homeostasis gene pathways. In addition, the innovative methods used in these genetic analyses demonstrate a method that may be employed by other research groups interesting in the use of gene expression for association analyses.
Future research could proceed in several directions. Use of a validated instrument adds a measure of confidence to a study and is essential for collection and interpretation of accurate patient data. However, due to the data available, a full description of the reliability and validity of the SSCSI was not possible. Before the SSCSI is used in full-scale studies, it must be tested in other samples of children and adolescents with ASD in order to establish test-retest reliability, inter-rater reliability, and to support our findings of internal consistency. The SSCSI must also be used along with validated sleep questionnaires such as the Children’s Sleep Habits Questionnaire, Modified Simmons and Parraga Sleep Questionnaire, or the Clinical Global Index-Sleep in order to establish convergent validity. In addition to refining the SSCSI, use of objective measures of sleep, such as actigraphy and polysomnography, would provide a strong foundation for association studies. As a next-step toward translation of research results into clinical
practice, evaluation of screening for sleep problems in various clinical settings may be performed to document how often healthcare providers address sleep problems.
Continued research into the genomics of sleep problems in individuals with ASD are clearly needed. The lack of association found between expression of genes and sleep patterns in the present study does not imply that the melatonin synthesis and SCN pathway should be abandoned. Although this study showed that transcription of these genes was not influencing sleep patterns, the effect of translation and post-translational modification on melatonin and SCN proteins cannot be dismissed. That a number of research studies have shown low melatonin or melatonin metabolite levels demonstrates this is still a valid research area. Expanding on recent research suggesting that risk for ASD may lie in common variants acting additively, it may be informative to investigate risk haplotypes from melatonin-synthesis genes or SCN genes as guided by literature and well-thought out hypotheses. However, as other gene pathways in the brain and body, such as glutamate, GABA, and serotonin are known to interact with melatonin and the SCN, inquiries should not be limited to the melatonin/SCN pathway. In summary, future research into the biological basis of sleep problems in ASD—genetic, biochemical, comorbid conditions—and the effect of therapies on sleep problems may move this research into the realm of clinical interventions to improve quality of life for families affected by ASD and sleep problems.
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