Clinical Features of Children Roald A. Øien, MA,a,​ ​b Synnve Schjølberg, Cand.psych,c​ Fred R. Volkmar, MD,b​ Frederick Shic, PhD,d,​ ​e Domenic V. Cicchetti, PhD,b​ WithAnders Nordahl-Hansen, Autism PhD,f​ Nina Stenberg, Who PhD,g​ Mady Passed Hornig, MD,​h,i​ Alexandra Havdahl, PhD,c,​ ​j Anne-Siri Øyen, PhD,c,​ ​k b h,l​ a b 18-MonthPamela Ventola, PhD,​ Ezra S. Susser, Screening MD,​ Martin R. Eisemann, PhD,​ Katarzyna Chawarska, PhD

OBJECTIVES: abstract

We compared sex-stratified developmental and temperamental profiles at 18 months in children screening negative for autism spectrum disorder (ASD) on the Modified Checklist for Autism in Toddlers (M-CHAT) but later receiving diagnoses of ASD METHODS: (false-negative group) versus those without later ASD diagnoses (true-negative group). We included 68197 screen-negative cases from the Norwegian Mother and Child Cohort Study (49.1% girls). Children were screened by using the 6 critical items of the M-CHAT at 18 months. Groups were compared on domains of the Ages and Stages RESULTS: Questionnaire and the Emotionality Activity Sociability Temperament Survey. Despite passing M-CHAT screening at 18 months, children in the false-negative group exhibited delays in social, communication, and motor skills compared with the true-negative group. Differences were more pronounced in girls. However, with regard to shyness, boys in the false-negative group were rated as more shy than their true-negative counterparts, but girls in the false-negative group were rated as less shy than their CONCLUSIONS: counterparts in the true-negative group. This is the first study to reveal that children who pass M-CHAT screening at 18 months and are later diagnosed with ASD exhibit delays in core social and communication areas as well as fine motor skills at 18 months. Differences appeared to be more pronounced in girls. With these findings, we underscore the need to enhance the understanding of early markers of ASD in boys and girls, as well as factors affecting parental report on early delays and abnormalities, to improve the sensitivity of screening instruments.

WHAT’S KNOWN ON THIS SUBJECT: To our best knowledge, no researchers have examined the a b Department of Psychology, University of Tromsø – The Arctic University of Norway, Tromsø, Norway; Child clinical characteristics of children who pass Study Center, School of Medicine, Yale University, New Haven, Connecticut; cDivision of Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway; dCenter for Child Health, Behavior, and Development, screening for autism spectrum disorder (ASD) at 18 Seattle Children’s Research Institute, Seattle, Washington; eDepartment of Pediatrics, School of Medicine, months but are later diagnosed with the disorder. University of Washington, Seattle, Washington; fDepartment of Special Needs Education, University of Oslo, Oslo, Norway; gDivision of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; hDepartment of WHAT THIS STUDY ADDS: The current study reveals Epidemiology, and iCenter for Infection and Immunity, Mailman School of Public Health, Columbia University, that despite passing screening for ASD, 18-month- New York, New York; jMedical Research Council Integrative Epidemiology Unit, Bristol Medical School, University old boys and girls who are later diagnosed with k l of Bristol, Bristol, United Kingdom; Nic Waals Institute, Lovisenberg Hospital, Oslo, Norway; and New York State ASD show delays and atypical features in social, Psychiatric Institute, New York, New York communication, and motor domains at the time of Mr Øien, Mrs Schjølberg, and Drs Volkmar, Shic, and Chawarska conceptualized and designed the the screening. study, conducted the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Havdahl, Nordahl-Hansen, Hornig, Stenberg, Øyen, Ventola, Susser, and Eisemann edited and critically reviewed the manuscript and its analyses; Dr Cicchetti supervised and critically reviewed the analyses and reviewed the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. To cite: Øien RA, Schjølberg S, Volkmar FR, et al. Clinical DOI: https://​doi.​org/​10.​1542/​peds.​2017-​3596 Features of Children With Autism Who Passed 18-Month Screening. Pediatrics. 2018;141(6):e20173596

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 6, June 2018:e20173596 ARTICLE 7,11,​ 12​ The primary goal of autism are at risk for ASD. ‍ ‍ A critical passed the 6-critical-item criterion spectrum disorder (ASD) screening gap in the current evidence stems of the M-CHAT at 18 months but instruments is to facilitate the early from a lack of prospective follow-up went on to receive an ASD diagnosis. identification and implementation studies of1 children who screen Specifically, we compared screen- of early interventions. However, negative. negative children without a later because most studies are conducted ASD diagnosis (true-negative To the best of our knowledge, no in clinical populations, it is unclear group) to screen-negative children researchers have yet investigated the if existing screening instruments with a later ASD diagnosis (false- developmental and temperamental have sufficiently high sensitivity, negative group) on a set of characteristics of children who specificity, and positive predictive developmental and temperamental screen negative on the basis of the value (PPV) in general population- features that were also measured at 1,2​ M-CHAT at 18 months of age but based samples. ‍ Furthermore, age 18 months. We capitalized on later receive an ASD diagnosis. there is increasing awareness of data collected through the Norwegian Understanding how early symptoms substantial heterogeneity with Mother and Child Cohort Study manifest in this group of children 24 respect to both the timing of the (MoBa),​ which is a prospective, 3 is of paramount significance for onset of recognizable symptoms and countrywide pregnancy cohort of 4 the development of future ASD- patterns of symptom expression. parents who were recruited at the specific screening instruments. Recognizing that symptoms of ASD 18th gestational week ultrasound There are multiple reasons why may become apparent at different examination and were managed ’ a child with ASD may pass early ages as social demands begin to regularly with questionnaires screening only to be diagnosed exceed a child s limitations, the strict related to child development. with ASD later in childhood, apart 7 age-of-onset criterion in previous The M-CHAT,​ along with other Diagnostic and from simply experiencing later formal definitions of ASD has been developmental scales, was part of Statistical Manual of Mental Disorders, symptom onset. Limited parental removed from the the 18-month MoBa questionnaire. Fifth Edition knowledge or understanding of the The examination of characteristics 5 screening questions may also be an . Moreover, recent in screen-negative children may issue, although recent studies have prospective studies of infants who facilitate the identification of revealed good agreement between are at familial risk for ASD reveal new behavioral markers of ASD parents and clinicians on ratings of that symptoms of ASD may manifest at critical time points for the ’ autism-related behaviors among somewhat differently depending on a emergence of frank behavioral the parents of infants who are at child s verbal and nonverbal levels of 13,14​ symptoms of ASD. 6 risk for ASD. ‍ Studies also reveal functioning. METHODS that child-related factors such15 as better developed language,​ the The Modified Checklist for Autism Study Population 7 absence of repetitive and restricted in Toddlers (M-CHAT) is the most behaviors, average-range IQ, younger widely used screening instrument for 16,17​ 8 age at assessment,​ and lack of ASD in young children. Designed to 18 The study sample is derived from additional behavioral issues may 24 be completed in the waiting room of the MoBa. In total, 40.6% of invited 7 mask symptoms of social disability. a primary care provider,​ it has been mothers consented to participate. Incorporating other measures recommended for use in toddlers at Diagnoses of ASD were obtained from that can be used to more broadly 18 months of age with a follow-up ’ the Autism Birth Cohort (ABC), which 9 examine developmental features and 25 at 24 months. Although studies is a substudy in the MoBa in which consider children s developmental of the M-CHAT typically reveal its researchers integrated diagnoses levels could provide new insights high sensitivity in clinical samples, from ABC clinic assessments at with regard to earlier identification it has been criticized for its lower child age 40 months and older and of children with ASD. Moreover, specificity and PPV. In an unselected diagnoses obtained through annual 10 given multiple reports revealing population sample, Stenberg et al – linkage with the Norwegian Patient ’ sex differences in syndrome reported a PPV of 3.3% using the 19 23 Registry (NPR). The NPR is a national expression,​ ‍ ‍ there is great M-CHAT s 6-critical-item criterion database of all discharge diagnoses need to evaluate the performance and 1.5% using the total 23-item of patients who are assessed in of existing screens in both boys criterion in a general population health care services across Norway. and girls. sample. In selected populations It has been available since 2008. (ie, children with developmental In the current study, we examined According to national guidelines for concerns), the M-CHAT performs developmental and temperamental specialist health care in Norway, better in detecting children who characteristics of children who the use of the Autism Diagnostic Downloaded from www.aappublications.org/news by guest on October 1, 2021 2 ØIEN et al Observation Schedule and Autism Diagnostic Interview-Revised in the diagnostic process is mandatory, together with a range of other tests and/or interviews related to cognitive and adaptive function. The researchers in the MoBa and ABC study obtained written, informed consent from participating mothers and were granted approval from the Norwegian Data Inspectorate as well as the Regional Committees for Medical and Health Research Ethics, Southeast Norway. In the current study, we used the MoBa data release version 9, reflecting diagnoses collected throughout Measures2015 (Fig 1). FIGURE 1 Sample inclusion and exclusion information. MoBa questionnaires completed when the child was 18 months old TABLE 1 Number of Cases and Mean (SD) of Participant’s Age at Time of Screening and of Failed included the M-CHAT, selected M-CHAT 6 Critical Items items from the Ages and Stages 26 Total True- True- True- Total False- False- Questionnaire (ASQ) and the Negative Negative Negative False- Negative Negative Emotionality Activity Sociability27 Cases Boys Girls Negative Boys Girls Temperament Survey (EAS). The Cases

M-CHAT is a7 23-item screening instrument,​ with each item scored No. cases 67 969 34 502 33 467 228 192 36 either as pass or fail. Six of the Age at time of 18.53 (0.62) 18.53 (0.64) 18.53 (0.60) 18.51 18.51 18.53 screening, mo (0.55) (0.56) (0.48) 23 items are considered critical 7 Failed M-CHAT 6 0.10 (0.30) 0.12 (0.32) 0.08 (0.28) 0.27 (0.44) 0.25 (0.43) 0.41 for predicting an ASD diagnosis critical items (0.50) because the items probe for social and communicative behaviors such as pointing, interest in other 26 children, imitation, and response to 4 months to 5 years. For each characteristic and/or typical of his or her own name (Supplemental item, parents are asked to rate your child] to 5 [not characteristic “ ” Information). whether specific behaviors are and/or typical of your child]). A ≥ “ ” “ 29 currently present: yes (10), subset of 11 items of the EAS Children are considered to have ” screened positive if they fail 2 of present sometimes (5), and not falling into 4 EAS-defined domains the 6 critical items. For the purpose yet present (0). Thus, a higher (sociability, shyness, activity, and of this study, individual scores on the score indicates more normative emotionality) were included in 6 critical items were summarized, development. A subset of 13 items the MoBa 18-month questionnaire and children receiving scores <2 falling into 4 ASQ-defined domains (Supplemental Figure 4). Items were were categorized as having screened (social, communication, fine motor, coded such that a higher score on negative. The focus on the 6 critical and gross motor) were included in all domains indicated more sociable items was motivated by findings the MoBa 18-month questionnaire and active traits and less shy and (Supplemental Figure 3). emotional traits. that this criterion provides the7,10,​ best11,​ 28​ Statistical Analyses 27 precision for predicting ASD. ‍ ‍ ‍ The EAS was designed for children The means of the 6 critical items are aged 1 to 9 years and measures listed in Table 1. emotionality, activity, sociability, and To compare children in the true- The ASQ is a parent-reported shyness. For each item, the parent negative group to children in the questionnaire designed to measure is asked to rate his or her child on false-negative group, we conducted a developmental skills from ages a 5-point rating scale (from 1 [very set of univariate analyses of variance Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 6, June 2018 3 FIGURE 2 A, Mean (±1 SE) of the ASQ scores for false-negative and true-negative boys. *** P < .001. B, Mean (± 1 SE) of the ASQ scores for false-negative and true- negative girls. *** P < .001; ** P < .010. C, Mean (±1 SE) of the EAS scores for false-negative and true-negative boys. *** P < .001; ** P < .010. Higher scores on the shyness and emotionality scales indicate less shy and emotional presentation; higher sociability and activity scores indicate more pronounced characteristics in this domain. D, Mean (±1 SE) of the EAS scores for false-negative and true-negative girls. * P < .050. Higher scores on the shyness and emotionality scales indicate less shy and emotional presentation; higher sociability and activity scores indicate more pronounced characteristics in this domain.

with diagnosis (ASD and no ASD) and provided a measure of effect sizes in negative. Among those screening ’ d sex (male and female) as between- the independent samples analyses. negative, 49.1% were girls. Of the group factors on the ASQ and EAS Cohen s was interpreted as follows: 68197 screen-negative children, 228 domain scores. Post hoc analyses T (trivial), S (small),30 M (moderate), (15.8% girls) were later diagnosed were conducted for between- and and L (large). with ASD (false-negative children; within-group differences by using RESULTS Developmental‍Figs 2A and 2B). Domains (ASQ) independent samples. Analyses in which we compared true-positive to Social Domain false-negative results are attached Of the 69668 children with all 6 (Supplemental Figure 5). Bonferroni critical items completed at the ’ d P correction was used to control for 18-month screening, 1471 screened Analyses revealed a significant effect multiple comparisons, and Cohen s positive and 68197 screened of diagnosis ( < .001), no effect Downloaded from www.aappublications.org/news by guest on October 1, 2021 4 ØIEN et al TABLE 2 Mean (SD) of the ASQ Scores for Boys and Girls in the True-Negative and False-Negative Groups P N ASQ Social ASQ ASQ Fine Motor ASQ Gross Motor dfalse-negative and true-negative Communication boys in gross motor skills ( < .001; = 0.267[S]) as well as between the Boys: true- 33 163 9.32 (1.18) 7.51 (2.64) 9.39 (1.27) 9.49 (1.40) P d negative false-negative and true-negative girls Girls: true- 32 231 9.59 (0.94) 8.44 (2.21) 9.28 (1.37) 9.46 (1.49) ( < .001; = 1.06[L]). The magnitude negative of the effect was greater in girls. Girls Boys: false- 183 8.88 (1.66) 5.71 (3.26) 8.76 (1.78) 8.83 (2.29) in the false-negative group had lower negative P d Girls: false- 33 8.48 (2.18) 5.20 (3.40) 8.28 (2.34) 6.36 (3.85) scores than boys in the false-negative negative group ( = .001; = 0.779[M]), andP true-negatived girls had lower scores than true-negative boys TABLE 3 Mean (SD) of the EAS Scores for Boys and Girls in the True-Negative and False-Negative ( = .005; = 0.022[T]; Figs 2C Groups Temperamentaland 2D). Characteristics N EAS Sociability EAS Shyness EAS EAS Activity (EAS Subdomains) Emotionality Sociability Boys: true-negative 33 300 3.95 (0.55) 3.99 (0.62) 3.25 (0.75) 4.08 (0.64) Girls: true-negative 32 347 3.96 (0.55) 3.91 (0.65) 3.27 (0.76) 3.96 (0.64) Boys: false- 185 3.96 (0.59) 3.84 (0.71) 3.18 (0.79) 4.05 (0.71) negative P Analyses revealed a significant Girls: false- 36 3.83 (0.63) 4.14 (0.59) 3.09 (0.79) 3.75 (0.86) P negative effect of diagnosis P( < .001), no Higher scores on the shyness and emotionality scales indicate less shy and emotional presentation; higher sociability and effect of sex ( = .156), and no activity scores indicate more pronounced characteristics in this domain. interaction effect ( = .260; Table 3). Post hoc analyses P P d revealed that children in the false-negative group were rated ofP sex ( = .551), and a significant ( < .001; = 1.13[L]). The magnitude as less sociable than childrenP diagnosis-by-sex interaction of the effect was greater in girls. No in the true-negative group ( = .001; Table 2). Boys in the differencesP were foundd between regardless of their sex ( < .001; false-negativeP d group were rated as boys and girls in the false-negative dShyness = 0.403[S]). less social than true-negative boys groups ( = .414; = 0.152[T]),P but ( < .001; = 0.303[S]). Girls in the true-negative girls scored higher d P false-negative group were also rated than true-negative boys ( < .001; P AnalysesP revealed no effects as having fewer social skills than = 0.380[S]). d Fine Motor Domain of diagnosis ( = .551)P or sex true-negative girls ( = .007; ( = .060) but a significant diagnosis- = 0.657[M]), but the magnitude of by-sex interaction ( = .001). Post P the difference was larger than that Analyses revealed significant effects hoc analyses revealed that boys observed in boys. No significant P of diagnosis ( < .001) and sex in the false-negative groupP were differences were found between P P d ( = .017) but no interaction between drated as more shy than boys in boys and girls in the false-negative the factors ( = .152). Children in the true-negative group ( = .003; group ( = .329; = 0.203[S]). the false-negative group had, = 0.238[S]). Girls in the false- However, true-negative girls had negative group were rated as less shy P in general, less developedP fine P d higher scores on social skills than than girls in the true-negative group d dmotor skills than children in true-negative boys ( < .001; the true-negative group ( < .001; ( = .035; = 0.369[S]). Girls Communication = 0.255[S]). Domain in the false-negative group were = 0.399[S]). GirlsP were generally P rated as less shy than boys in the dless advanced in fine motor d P skills than boys ( < .001; false-negative group ( = .017; AnalysesP revealed a significant = 0.088[T]) regardless of = 0.463[S]). Furthermore, girls effect of diagnosis (P < .001), no effect diagnosis.Gross Motor Domain in the true-negative groupP were of sex ( = .366), and a diagnosis- drated as more shy than boys in the by-sex interaction ( = .002). P true-negative group ( < .001; Emotionality There was a difference betweenP the AnalysesP revealed significant = 0.134[T]). dfalse-negative and true-negative boys effects of diagnosisP ( < .001) and in communication skills ( < .001; sex ( < .001) and a diagnosis-by- P = 0.608[M]) as well as between the sex interaction ( < .001). There Analyses revealed no significant false-negative and true-negative girls was a differences between the effects of diagnosis ( = .069), sex Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 6, June 2018 5 P P ( = .607), or interaction between cases may already be present at with ASD. Future researchers diagnosisActivity and sex ( = .435). 18 months. There were no marked should examine the levels of social differences between boys and fearfulness and inhibitory control P girls because in most cases, both during infancy and early childhood in AnalysesP revealed significant boys and girls in the false-negative ASD because these processes have a effects ofP diagnosis ( = .036) and group performed poorer than their great capacity to shape the emerging sex ( < .001) but no interaction sex-matched counterparts in the autism phenotypes and contribute effects ( = .114). Post hoc analyses true-negative group. However, the to the heterogeneity in syndrome revealed no difference between observed differences, as indexed expression. childrenP in the false-negative by effect sizes, appeared more and true-negative groupsP pronounced in girls, particularly The results also revealed sex (d = .664). Girls were, in general, in the social, communication, and differences that were independent less active than boys ( < .001; gross motor domains. There was of the ASD outcome. Specifically, = 0.183[T]) regardless of only 1 area in which boys and girls boys in both groups were more diagnosis. showed a different pattern: boys advanced than girls in gross DISCUSSION in the false-negative group were motor skills, a finding that is rated as more shy than boys in consistent with findings in 35,earlier36​ the true-negative group, whereas work on children with ASD ‍

To the best of our knowledge, girls in the false-negative group as well as37, in38​ typically developing this study is the first in which were rated as less shy than girls children. ‍ Furthermore, 21,39​ researchers investigate the in the true-negative group. consistent with previous work,​ ‍ concurrent developmental and These findings reveal that at boys had a higher activity level temperamental characteristics 18 months, there are already than girls. of boys and girls who pass the nuanced differences in 6-critical-item criterion of the temperamental indices between The current study revealed that M-CHAT at 18 months of age boys and girls who screen despite passing the M-CHAT but ultimately receive an ASD negative and later receive an 6-critical-item criterion, 18-month- diagnosis at a later age. Using ASD diagnosis. old false-negative children show a large prospective population atypical features compared with study, we compared children with Intriguingly, girls in the false- children in the true-negative false-negative screen results to negative group were rated as less group. Importantly, the M-CHAT, true-negative children on their socially inhibited compared with ASQ and EAS were completed by characteristics as measured boys. This is in contrast to the parents around the same age of concurrently with M-CHAT pattern found in the true-negative the child, and thus, recall bias and screening at 18 months. group. A closer inspection of the hindsight are unlikely to explain shyness domain revealed that girls these disparities. At present, it Despite screening negative for in the false-negative group had is not clear what contributed to ASD on the M-CHAT, children in shorter warm-up time and appeared the observed differences among the false-negative group exhibited friendlier toward strangers than instruments, but several hypotheses delays and atypical features boys in the false-negative group can be advanced. First, parents compared with children in the true- (Supplemental Figure 3). We may have difficulties mapping negative group. Specifically, children hypothesize that girls in the false- the specific behavioral markers ’ in the false-negative group were negative group have somewhat lower considered in the M-CHAT onto already rated by their parents at levels of social fearfulness or lower their children s real-life behaviors. 18 months as having less developed inhibitory control compared with They may also have difficulties social and communication skills boys. Studies have revealed that in understanding some of the as well as showing fine and gross typically developing children, girls phenomenology of more specific motor delays compared with show greater inhibitory32 control or rare behaviors related to ASD. children in the true-negative compared with boys. The sparse Moreover, M-CHAT items do not group. The domains of impairment research on inhibitory control in provide opportunities for graded identified in the current study map individuals with ASD also reveals responses, which might affect onto those found in children with that girls with33,34​ ASD express less how parents weigh their answers. autism diagnosed6,31​ in the second inhibition,​ ‍ and there is a lack of The ASQ gives parents the year of life,​ ‍ revealing that atypical knowledge about sex differences in opportunity to express that the features in the false-negative fearfulness among young children children exhibit skills occasionally Downloaded from www.aappublications.org/news by guest on October 1, 2021 6 ØIEN et al albeit inconsistently, which may has new cutoffs and a recommended M-CHAT R/F, this novel finding allow them to express their concerns follow-up interview to provide adds critical knowledge to our and perceptions in a more graded greater utility at the diagnostic understanding of the role of sex in manner. Finally, it is also likely that margins. The newly proposed shaping early autistic phenotypes, symptoms of ASD may be expressed M-CHAT R/F cutoffs reveal improved and we highlight the importance of ’ differently in early childhood ASD detection and diminished considering sex differences in early depending on a child s specific 6 rates of false-positives. However, screening and diagnosis. In this level of verbal and nonverbal skill given the lack of a comprehensive study, we also expand state-of-art or temperamental characteristics. prospective follow-up of screen- pediatric practice by emphasizing Another study utilizing a large negative cases, it is not clear that when trying to determine if sample of infants at risk for whether these changes also led a young child is exhibiting autism ASD revealed that at 18 months, to decreased false-negative rates. symptoms, clinicians should not children who display more Considering that population- rely solely on a single instrument prototypical symptoms of ASD based studies that are focused on but consider parental concerns tend to have lower verbal and screening for developmental and draw on other developmental nonverbal skills than those who disorders and incorporate long- surveillance instruments as 43 are later diagnosed with ASD but term follow-up of all recruits are well as their clinical judgment. show presentation6 at 18 months rare and take a long time to complete, The clinicians also need to be is less typical. To date, few ASD- it may be some time before the particularly wary about discounting specific screening instruments M-CHAT R/F will be scrutinized symptoms of social difficulties provide accommodations or in a similar fashion as the original in girls because they maybe modifications for variation in M-CHAT. masked by limited shyness or language level, although direct social inhibition. diagnostic measures such as the We believe that our results Autism Diagnostic Observation contribute, at a fundamental level, Limitations of the current study Schedule, Second Edition consider to our understanding of early include the lack of concurrent verbal level when selecting the screening for ASD, and we highlight direct measures of verbal and algorithm items that are most the discrepancy between hard nonverbal developmental levels likely40 to identify children with cutoff criteria for autism and and absence of data regarding ASD. However, there are ongoing the social-communicative, the severity of autism symptoms efforts to develop autism screens developmental, and temperamental (eg, Autism Diagnostic Observation that41, are42​ sensitive to chronological signatures of emerging or Schedule, Second Edition or age. Similarly, future subthreshold autism phenotypes. Autism Diagnostic Interview- researchers should examine This issue will likely be universal Revised). Furthermore, the directly the effects of cognitive to all parent-directed screening measures used in the present and temperament variables on efforts for the foreseeable future. investigation were restricted to early phenotypic expression of Further research using measures subsets of items from the ASQ

ASD and evaluate if taking these that incorporate6 levels of verbal and and EAS, making it difficult to under consideration may improve nonverbal skill and temperamental use cutoffs for clinical concern. early detection. characteristics may prove useful Researchers in future replication

7 for the development of screening studies should strive to include It should be noted that the M-CHAT instruments with an improved full-scale measures. The strengths screen used in the current study capacity for identifying children of the study include the prospective has undergone recent revisions, on the autism spectrum in the design of the MoBa, the data from leading to the introduction of the second year of life. There is also a an unselected general population, Modified Checklist for Autism in need to optimize screener design and the ability to examine outcomes

Toddlers Revised12 With Follow-Up and delivery to fully capitalize of negative screen results across (M-CHAT R/F),​ which is aimed on parental knowledge of their time by identifying children with at decreasing positive screen children. The results also reveal a ASD at later time points through results while retaining sensitivity. unique quality of girls who screen the NPR. Researchers in future The number of questions in the negative but are later diagnosed prospective population studies M-CHAT was decreased by 3, and with ASD, namely diminished should also conduct screening at the 6-critical-item criterion was shyness or social inhibition. Given 24 months of age, according to abandoned such that the M-CHAT that these dimensions are not American Academy of Pediatrics R/F now consists of 20 items and captured by either the M-CHAT or guidelines on screening. Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 6, June 2018 7 CONCLUSIONS ABBREVIATIONS questions involve whether the range of response options provided for This is the first study to reveal that each item is sufficiently granular and ABC: Autism Birth Cohort despite passing the autism-specific if new or adapted screening items ASD: autism spectrum disorder screening at 18 months, both boys ASQ: Ages and Stages and girls who later receive a diagnosis might improve the capture of the Questionnaire of ASD show delays and atypical early symptom profiles found here EAS: Emotionality Activity features in social, communication, or identify characteristics of lower- Sociability Temperament and motor domains. This information and higher-functioning13 subsets of Survey was collected via parent report children. To maximize opportunities MoBa: Norwegian Mother and concurrently to the autism-specific for early ascertainment of the broader Child Cohort Study screening. These findings reveal that range of children who will ultimately M-CHAT: Modified Checklist for there is a pressing need for enhancing receive an ASD diagnosis, screening Autism in Toddlers our understanding of how to improve instruments should be refined to M-CHAT R/F: Modified Checklist screening instruments, including an improve their capacity for identifying for Autism in evaluation of how well the intended the patterns of deficits that appear Toddlers Revised meanings of items are understood to emerge in early life among these With Follow-Up and interpreted by parents and how later-diagnosed children who escape NPR: Norwegian Patient Registry patterns of atypical behavior stratify detection by current screening PPV: positive predictive value developmentally by sex. Key future algorithms. Accepted for publication Mar 5, 2018 Address correspondence to Roald A. Øien, MA, Department of Psychology, UiT – The Arctic University of Norway, PB 6050, 9037 Tromsø, Norway. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Hornig is a coinventor on a patent on an intestinal microbiome biomarker for autism assigned to Columbia University (US patent number 9050276) and on patent applications based on another set of proposed autism-associated biomarkers also assigned to Columbia University (US patent application number 20170328917, international Patent Cooperation Treaty application number PCT/US2013/028589, and WO2010147714A1). No funding has been received from these patents at the time of the writing of this article; the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: The data set used in these analyses was derived from the Norwegian Mother and Child Cohort Study and its substudy of autism spectrum disorders, the Autism Birth Cohort Study. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, the Research Council of Norway and Functional Genomics in Norway (grant 151918), the National Institute of Neurological Disorders and Stroke (grant NS47537), and the National Institute of Environmental Health Sciences (contract NO-ES-75558; Research Triangle Park, NC). Mr Øien is supported by the University of Tromsø – The Arctic University of Norway. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. COMPANION PAPER: A companion to this article can be found online at www.pediatrics.​ ​org/​cgi/​doi/​10.​1542/​peds.​2018-​0965.

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Downloaded from www.aappublications.org/news by guest on October 1, 2021 10 ØIEN et al Clinical Features of Children With Autism Who Passed 18-Month Screening Roald A. Øien, Synnve Schjølberg, Fred R. Volkmar, Frederick Shic, Domenic V. Cicchetti, Anders Nordahl-Hansen, Nina Stenberg, Mady Hornig, Alexandra Havdahl, Anne-Siri Øyen, Pamela Ventola, Ezra S. Susser, Martin R. Eisemann and Katarzyna Chawarska Pediatrics 2018;141; DOI: 10.1542/peds.2017-3596 originally published online May 21, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/141/6/e20173596 References This article cites 36 articles, 4 of which you can access for free at: http://pediatrics.aappublications.org/content/141/6/e20173596#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Developmental/Behavioral Pediatrics http://www.aappublications.org/cgi/collection/development:behavior al_issues_sub Autism/ASD http://www.aappublications.org/cgi/collection/autism:asd_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 Clinical Features of Children With Autism Who Passed 18-Month Screening Roald A. Øien, Synnve Schjølberg, Fred R. Volkmar, Frederick Shic, Domenic V. Cicchetti, Anders Nordahl-Hansen, Nina Stenberg, Mady Hornig, Alexandra Havdahl, Anne-Siri Øyen, Pamela Ventola, Ezra S. Susser, Martin R. Eisemann and Katarzyna Chawarska Pediatrics 2018;141; DOI: 10.1542/peds.2017-3596 originally published online May 21, 2018;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/141/6/e20173596

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