Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study

In the paper

“Examination of simple effects revealed that both males and females showed similar trajectories among different subscales, with visual reception scores rising significantly more rapidly than other subscales, fine motor rising significantly more slowly than other subscales, and both language subscales rising at intermediate rates.”

In the paper

“The two non-ASD groups did not differ in their visual reception and receptive language trajectories, but the HR non-ASD group had significantly slower growth in fine motor and expressive language when compared to the LR non-ASD group.”

In the paper

“likewise, 2.4 % of HR-ASD, 17.2 % of HR-No-ASD, and 14.2 % of LR ASD were missing.”

In the paper

“The female advantage for significant comparisons at each age ranged from 1.06 to 3.3 months on age-equivalent scores; effect sizes ranged from medium to large (d range .33 to .54).”

In the paper

“At 36 months, 14.1 % of male and 14.3 % of female ADOS were missing;”

In the paper

“On the ADOS, for example, 13.9 % of data were missing at 24 months and 14.2 % were missing at 36 months.”

In the paper

“Proband sex was not associated with ASD symptom severity or cognitive functioning, a pattern which does not implicate a female protective effect.”

In the paper

“Similarly, for multiplex status, there was no main effect (X2 = 0.66, df = 1, p = .42), and no interaction with infant sibling sex (X2 = 0.18, df = 1, p = .67) or with group (X2 = 0.97, df = 1, p = .33).”

In the paper

“However, multiplex status did not interact with group (X2 = 0.02, df = 1, p = .88) or with infant sibling sex (X2 = 1.35, df = 1, p = .25).”

In the paper

“For the MSEL subscales, proband sex did not have a significant main effect (X2 = 1.42, df = 1, p = .23), nor did it interact with group (X2 = 0.69, df = 1, p = .41) or with infant sibling sex (X2 = 0.13, df = 1, p = .72).”

In the paper

“At 24 months, the HR non-ASD group was significantly higher than the LR non-ASD group in both the RRB and SA domains but, at 36 months, was only higher in the RRB domain.”

• Also stated in: § Sex differences and the early ASD phenotype · plain

  “At 36 months, the high-risk group without ASD outcomes exhibited higher levels of restricted and repetitive behaviors, but not social affect difficulties, than the low-risk group.”

In the paper

“For slope comparisons between subscales within each outcome group, all three groups showed similar patterns of trajectories across the subscales, with the greatest increases in visual reception, the slowest increases in fine motor, and both language subscales showing intermediate growth over time.”

In the paper

“Across risk and outcome groups, girls performed better than boys in all dimensions of cognitive functioning assessed and exhibited a lower level of repetitive behavioral severity than boys.”

• Also stated in: § Conclusions · plain

  “Regardless of group membership, males exhibited lower levels of cognitive functioning than females and higher levels of restricted and repetitive behaviors.”

In the paper

“SA severity scores increased significantly for both the ASD and LR non-ASD groups between 24 and 36 months, but not for the HR non-ASD group.”

• Also stated in: § Sex differences and the early ASD phenotype · plain

  “While social affect severity scores increased for the HR ASD group, these children exhibited stable and elevated levels of restricted and repetitive behaviors between 2 and 3 years.”

In the paper

“With respect to group differences, as expected, children with ASD performed more poorly on cognitive subscales and exhibited higher levels of ASD-symptom severity than other children.”

• Also stated in: § Conclusions · plain

  “Children with ASD had lower levels of cognitive functioning and higher symptom severity levels than high-risk children without ASD who, in turn, exhibited lower cognitive functioning and higher ASD symptom severity than low-risk comparison children.”

In the paper

“The analysis data set contained 1824 infant participants, of whom 1241 were high-risk (HR) and 583 were low-risk (LR).”

• Also stated in: § Methods · plain

  “Prior to 18 months of age, 1824 infants (1241 high-risk siblings, 583 low-risk) from 15 sites were recruited.”

In the paper

“The odds ratio of ASD recurrence was 3:18 for male versus female high-risk siblings and was not impacted by proband sex.”

• Also stated in: § Sex differences in recurrence · plain

  “The 3.18:1 increased odds of ASD in males in the current sample (95 % CI = 2.31 to 4.39) is similar to estimates from community-based ascertainment of children (2.5:1–2.6:1) [5–7], as well as to a previous report on approximately half of the current high-risk sample [10].”

• Also stated in: § Conclusions · plain

  “This large prospectively ascertained sample of infants at high risk for ASD due to familial factors revealed a three-to-one male:female odds ratio in ASD recurrence.”

In the paper

“In brief, the sex by group interaction was not significant (p = .27), and there were no significant higher-order interactions involving sex and group (all p > .12).”

In the paper

“Proband sex did not affect ASD outcome, MSEL subscale, or ADOS domain scores.”

In the paper

“For the ADOS profile analyses, there was no significant main effect of proband sex (X2 = 0.09, df = 1, p = .76), and no interaction with infant sibling sex (X2 = 0.95, df =1, p = .33) or group (X2 = 0.19, df = 1, p = .66).”

In the paper

“The HR ASD group was significantly higher than each of the non-ASD comparison groups at both ages in both RRB and SA by between 2.25 and 4.31 points (all p < .001).”

In the paper

“Regardless of group, males obtained lower MSEL subscale scores, and higher ADOS RRB scores, than females.”

In the paper

“The HR-ASD group had lower MSEL subscale scores and higher RRB and SA scores than the HR non-ASD group, which had lower MSEL subscale scores and higher RRB scores than the LR group.”

In the paper

“Comparing group differences within subscales at each age, the HR ASD group scored significantly below the HR non-ASD group on all subscales at all ages (all p < .001), and the HR non-ASD group scored below the LR non-ASD group on all but one subscale (fine motor at 18 months) at all ages (all p < .001).”

In the paper

“Boys across all groups exhibited slower growth trajectories and lower levels of cognitive performance than girls in fine motor, visual reception, receptive and expressive language functioning.”

In the paper

“Nevertheless, an advantage in early cognitive functioning and lower levels of restricted and repetitive behaviors were both evident in females.”

In the paper

“The risks associated with a high-risk sibling being male and being from a multiplex status family were independent but cumulative.”

In the paper

“Challenging accounts of greater female affectedness, there was no evidence that girls exhibited lower levels of cognitive functioning or higher levels of symptom severity than boys.”

In the paper

“The 3.18:1 increased odds of ASD in males in the current sample (95 % CI = 2.31 to 4.39) is similar to estimates from community-based ascertainment of children (2.5:1–2.6:1) [5–7], as well as to a previous report on approximately half of the current high-risk sample [10].”

What the sources say

• Not checked yetcites [5] Honda H et al. Cumulative incidence of childhood autism: a total population study of better accuracy and precision. Dev Med Child Neurol. 2005;47(1):10–8. source
• Not checked yetcites [6] Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011;168(9):904–12. source
• Not checked yetcites [7] Idring S, Rai D, Dal H, Dalman C, Sturm H, Zander E, et al. Autism spectrum disorders in the Stockholm youth cohort: design, prevalence and validity. PLoS One. 2012;7(7), e41280. source
• Not checked yetcites [10] Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):15. source

In the paper

“Children with ASD exhibited elevated levels of both repetitive behaviors and disturbances of social affect with respect to HR siblings without ASD and low-risk children.”

In the paper

“Elevations in restricted and repetitive behavior were characteristic of all children with ASD and of boys relative to girls regardless of ASD or risk status.”

In the paper

“The male rate of ASD recurrence in the high-risk siblings was approximately 1 in 4 (26.7 %) while the female rate was 1 in 10 (10.3 %).”

In the paper

“Likewise, children with ASD outcomes, regardless of sex, exhibited slower growth trajectories and lower levels of performance than both high-risk and low-risk children without ASD.”

In the paper

“Given the small sample of female probands in multiplex families (n = 7), these analyses should be interpreted with caution,”

In the paper

“As such, estimates of profile scores may be biased slightly toward poorer functioning in the LR non-ASD and HR non-ASD groups, thereby making group comparisons slightly more conservative.”

In the paper

“Levels of missing data tended to be comparable for males and females and to be more common among LR and HR non-ASD than among the ASD group.”

In the paper

“These patterns suggest that high-risk status and the emergence of ASD indicators within the HR group are associated with less missing data.”

In the paper

“Thus male sex and multiplex status were each independently associated with an approximate 3:1 increase in the odds of ASD recurrence.”

In the paper

“For both the ADOS and MSEL, missing data were present at all ages for both sexes in all three groups.”

In the paper

“Age-equivalent scores are calibrated in months and are more sensitive to the low performance common in ASD samples than standard scores [17, 30].”

What the sources say

• Not checked yetcites [17] Hartley SL, Sikora DM. Sex differences in autism spectrum disorder: an examination of developmental functioning, autistic symptoms, and coexisting behavior problems in toddlers. J Autism Dev Disord. 2009;39(12):1715–22. source
• Not checked yetcites [30] Carter AS et al. Sex differences in toddlers with autism spectrum disorders. J Autism Dev Disord. 2007;37(1):86–97. source

In the paper

“Differences in the prevalence of ASD among males and females are among the most well-documented features of the disorder, but these sex differences vary by sample and ascertainment procedure [3, 8, 33].”

What the sources say

• Not checked yetcites [3] Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65(6):591–8. source
• Not checked yetcites [8] Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311(17):1770–7. source
• Not checked yetcites [33] Grønborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatr. 2013;167(10):947–53. source

In the paper

“and may have a higher threshold for the impact of the multifactorial array of genetic and environmental factors thought to be responsible for ASD [21].”

What the sources say

• Not checked yetcites [21] Werling DM, Geschwind DH. Sex differences in autism spectrum disorders. Curr Opin Neurol. 2013;26(2):146–53. source

In the paper

“Clinically identified girls with ASD carry a higher load of deleterious genetic variants than boys [20]”

What the sources say

• Not checked yetcites [20] Jacquemont S et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genet. 2014;94(3):415–25. source

In the paper

“Females with ASD have historically presented with lower IQ than boys [3, 12, 13].”

What the sources say

• Not checked yetcites [3] Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65(6):591–8. source
• Not checked yetcites [12] Volkmar FR, Szatmari P, Sparrow SS. Sex differences in pervasive developmental disorders. J Autism Dev Disord. 1993;23(4):579–91. source
• Not checked yetcites [13] Lord C, Schopler E, Revicki D. Sex differences in autism. J Autism Dev Disord. 1982;12(4):317–30. source

In the paper

“These 10-point severity scores allow for examining change in symptom severity over time as they are calibrated across different ages and test versions [28].”

What the sources say

• Not checked yetcites [28] Hus V, Gotham K, Lord C. Standardizing ADOS domain scores: separating severity of social affect and restricted and repetitive behaviors. J Autism Dev Disord. 2014;44(10):2400–12. source

In the paper

“However, a recent investigation did not reveal sex differences in cognitive performance or ASD symptom severity either among 3-year-olds with ASD or among typically developing children [15].”

What the sources say

• Not checked yetcites [15] Reinhardt VP, Wetherby AM, Schatschneider C, Lord C. Examination of sex differences in a large sample of young children with autism spectrum disorder and typical development. J Autism Dev Disord. 2015;45(3):697–706. source

In the paper

“ASD is more common in males than females [2], with an approximate 4:1 risk ratio estimate emerging both from literature review [3] and a school-based prevalence study of 8-year-olds [4].”

What the sources say

• Not checked yetcites [2] Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcín C, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5(3):160–79. source
• Not checked yetcites [3] Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65(6):591–8. source
• Not checked yetcites [4] Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention. Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, united states, 2010. MMWR Surveill Summ. 2014;63(SS02):1–21.

In the paper

“As sex differences were neither attenuated nor exaggerated among children with ASD, the results highlight the role of normative sex differences in the development of the autism phenotype.”

In the paper

“All sites used similar recruitment and sampling methodologies as well as standardized longitudinal diagnostic assessment procedures.”

In the paper

“and a non-significant male:female difference in a Swedish population cohort [8].”

What the sources say

• Not checked yetcites [8] Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311(17):1770–7. source

In the paper

“Likewise, females diagnosed with ASD in the Simons Simplex Collection exhibited higher levels of social affect and communication symptoms on the Autism Diagnostic Observation Schedule (ADOS) than males with ASD, as well as lower verbal and nonverbal IQ [14].”

What the sources say

• Not checked yetcites [14] Frazier TW, Georgiades S, Bishop SL, Hardan AY. Behavioral and cognitive characteristics of females and males with autism in the Simons Simplex Collection. J Am Acad Child Adolesc Psychiatry. 2014;53(3):329–340. source

In the paper

“Sex differences in cognitive performance and repetitive behaviors were apparent not only in high-risk children with ASD, but also in high-risk children without ASD and in low-risk children.”

In the paper

“A prospective investigation, for example, yielded some evidence of a female advantage (higher fine motor scores on the MSEL and lower ADOS severity scores) for high-risk siblings with an ASD outcome, high-risk siblings without an ASD outcome, and low-risk children [11].”

What the sources say

• Not checked yetcites [11] Zwaigenbaum L, Bryson SE, Szatmari P, Brian J, Smith IM, Roberts W, et al. Sex differences in children with autism spectrum disorder identified within a high-risk infant cohort. J Autism Dev Disord. 2012;28:28.

In the paper

“A previous report from the Baby Siblings Research Consortium (BSRC) utilizing slightly more than half (664) of the current sample of 1241 high-risk infants yielded an 18.7 % risk of ASD recurrence, which was elevated among males and among siblings from multiplex families [10].”

What the sources say

• Not checked yetcites [10] Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):15. source

In the paper

“In a subsequent BSRC report on non-diagnosed high-risk siblings [26], males in both high-risk (n = 507) and low-risk groups (n = 324) exhibited higher ASD symptom severity scores—and lower levels of verbal and nonverbal functioning—than females.”

What the sources say

• Not checked yetcites [26] Messinger D, Young GS, Ozonoff S, Dobkins K, Carter A, Zwaigenbaum L, et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. J Am Acad Child Adolesc Psychiatry. 2013;52(3):300–8. e1. source

In the paper

“Sex differences in young children with ASD do not appear to be ASD-specific but instead reflect typically occurring sex differences seen in children without ASD.”

In the paper

“To control for site differences in recurrence rates, site was included as a random effect.”

In the paper

“Two reports indicate that the siblings of female probands present with higher levels of parent-reported ASD symptoms than the siblings of male probands [16, 22].”

What the sources say

• Not checked yetcites [16] Szatmari P, Liu XQ, Goldberg J, Zwaigenbaum L, Paterson AD, Woodbury-Smith M, et al. Sex differences in repetitive stereotyped behaviors in autism: implications for genetic liability. Am J Med Genet B Neuropsychiatr Genet. 2012;159b(1):5–12. source
• Not checked yetcites [22] Robinson EB, Lichtenstein P, Anckarsäter H, Happé F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci U S A. 2013;110(13):5258–62. source

In the paper

“The instruments used to assess sex differences among multiple sites of Baby Sibling Research Consortium were relatively coarse-grained behavioral assays.”

In the paper

“Assessment of ASD outcome occurred at a fixed time point, 3 years of age, using both clinical best estimate diagnosis and ADOS criteria.”

In the paper

“Although a recent report on twins reported higher recurrence for siblings of female probands, probands (and affected siblings) were identified by thresholding (e.g., greater than 90th percentile) parent-reported autistic traits rather than by diagnosis [22].”

What the sources say

• Not checked yetcites [22] Robinson EB, Lichtenstein P, Anckarsäter H, Happé F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci U S A. 2013;110(13):5258–62. source

In the paper

“Although consonant with earlier reports from the sample [10], the number of multiplex cases (n = 77) was limited, suggesting that multiplex results should be interpreted with caution.”

In the paper

“Specification of this particular area of challenges for non-diagnosed high-risk siblings was not possible in reports of smaller subsets of this sample [26].”

What the sources say

• Not checked yetcites [26] Messinger D, Young GS, Ozonoff S, Dobkins K, Carter A, Zwaigenbaum L, et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. J Am Acad Child Adolesc Psychiatry. 2013;52(3):300–8. e1. source

In the paper

“Although the ADOS can function as an index of severity, it may have limited sensitivity to detect such subtle effects.”

In the paper

“Methodological strengths of the current study included prospective tracking of a large sample of 1241 high-risk siblings, 527 of whom were female, recruited by 18 months of age.”

In the paper

“Although a meta-analysis of clinical samples suggested that elevated levels of repetitive and stereotyped behaviors in males emerged only after age 6 [40], the current dataset affords a more fine-grained developmental perspective.”

What the sources say

• Not checked yetcites [40] Van Wijngaarden-Cremers PJ, van Eeten E, Groen WB, Van Deurzen PA, Oosterling IJ, Van der Gaag RJ. Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review and meta-analysis. J Autism Dev Disord. 2014;44(3):627–35. source

In the paper

“This pattern of results points to the potential clinical importance of prospective developmental designs in understanding sex differences in the emergence of autism.”

In the paper

“Recent findings highlight within family diversity in the de novo and rare inherited genetic mutations linked to sibling ASD [44].”

What the sources say

• Not checked yetcites [44] Yuen RKC, Thiruvahindrapuram B, Merico D, Walker S, Tammimies K, Hoang N, et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med. 2015;21(2):185–91. source