The January 2007 issue of the Journal of Autism and Developmental Disorders, dedicated to the “The Very Early Autism Phenotype,” includes 14 scientific manuscripts that describe ongoing research examining early signs of children later diagnosed with autism , and prospective studies on “at risk” infant siblings of children with autism. The research works to identify and ascertain early signs and behavioral impairments with the goal of identifying autism at the youngest age to make early intervention possible and effective.
All the articles in this issue were published by Autism Speaks-funded researchers, including those who are members of the Autism Speaks-funded High Risk Baby Siblings Research Consortium. Autism Speaks thanks Nurit Yirmiya and Sally Ozonoff, who organized this issue and who allowed us to re-publish the editorial preface for the Autism Speaks website.
The editorial preface describes the historical roots of this research and provides a detailed summary of each of the 14 articles, highlighting the different methodologies and emphasizing the importance of each contribution to the overall picture of earlier identification.
Editorial preface: The very early autism phenotype by Nurit Yirmiya1 and Sally Ozonoff2
1Department of Psychology and School of Education, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem, Israel 91905.
2MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, 2825 50th Street, Sacramento CA, 95817, USA.
Acknowledgments: We would like to thank Alice Kau, Ph.D., of the National Institute for Child Health and Human Development, Andrew Shih, Ph.D., of Autism Speaks, and members of the Baby Siblings Research Consortium, who participated actively in the networking that made this special issue possible. We also thank Gary Mesibov, Ph.D., and Kathie Barron for sharing the vision of this special issue with us.
In this editorial preface, we first describe the historical roots of this special issue. We then introduce the papers, all of which focus on the very early phenotype of autism and the broad autism phenotype. Some of the papers in this volume include studies on the very youngest children diagnosed with autism spectrum disorders (ASD) while in other papers the focus is on infant siblings of children with autism. Next, we discuss some methodological and clinical issues pertaining to the studies. We end by considering the ethics involved in these kinds of studies, their implications for prevention and intervention, and possible future directions. (In this paper, we use the term ASD to collectively refer to children meeting criteria for Autistic Disorder and Pervasive Developmental Disorder Not Otherwise Specified. When a distinction between these conditions is important, the specific term is used.)
In the mid-1980s, Marian Sigman, while on sabbatical in Europe, spoke with Sir Michael Rutter and Simon Baron-Cohen about initiating a young siblings study in order to achieve insight into the early precursors of autism. At that time, before the publication of the ADI-R and ADOS, Sir Michael Rutter was concerned that the older siblings with autism would not be diagnosed similarly across sites (and countries) and thus the group decided not to pursue this interest at that time. However, in the early 1990s, after publication of standardized diagnostic instruments that would make cross-site collaborations more reliable, Marian Sigman and Nurit Yirmiya initiated the first sibling study (Yirmiya, et al., 2005; Yirmiya, Gamliel, Shaked, & Sigman, 2006) in collaboration with Simon Baron-Cohen and Christopher Gillberg, who also collected data in the UK and Sweden. At the time, autism was estimated to occur in about 5 in every 10,000 live births, and the recurrence rate of autism in families was estimated at 4-8%, i.e., almost 100 fold that of the general population. Children were then diagnosed most often around age 3 years or older. Thus younger siblings were the optimal at-risk group for those interested in lowering the age of diagnosis. The hope was that earlier identification would lead to earlier intervention and a better prognosis.
Several research groups soon joined this research endeavour, leading to the establishment of the Baby Siblings Research Consortium (BSRC), a voluntary network of researchers studying infant siblings of children with autism and other very young children at risk for ASD. This consortium was first established in 2003 to bring together the major research groups in the field to discover the earliest behavioural and biomedical markers of ASD. The group currently consists of 18 accomplished scientists -- representing 16 research institutions across the US, Canada, and Israel -- who share a commitment to identify early markers and develop treatments for preventing or ameliorating symptom development and expression. Through collaborative research, ongoing communication, and regular networking opportunities, the group's ultimate goal is to optimize developmental outcomes for children with autism and enhance family adaptation. Many of the authors of papers in this issue are members of the BSRC.
This special section on the very early phenotype of autism is, in part, also the product of a symposium presented at the 2005 Biennial Meeting of the Society for Research in Child Development. Six of the papers in this issue were first presented in Atlanta in April 2005, but it was clear from the symposium's attendance and the lively discussion that took place afterwards that many other groups are conducting research in related areas. Thus, the idea for this special issue was hatched. We decided to solicit papers from groups currently engaged in work relevant to the earliest identification of autism and characterization of the very earliest evident phenotype. Other important work on early identification and the earliest behavioral signs of autism that is not represented in this volume is also being done ( Charman et al., 2005; Chawarska, Klin, & Volkmar, in press; Dietz, Swinkels, van Daalen, van Engeland & Buitelaar, 2006; Swinkels, Dietz, van Daalen, Kerkhof, van Engeland & Buitelaar, 2006).
The empirical contributions
The resulting fourteen papers comprising this special issue represent research that is the state of the art in the field of early detection and identification of autism and autism spectrum disorders and the broad phenotype of ASD in very young children. Eight papers focus on young children with ASD, employing either samples of siblings of children with autism who were followed prospectively from a young age and who at age 24-36 months were themselves diagnosed with an ASD (Bryson et al, Loh et al., Sullivan et al.) or on very young children newly diagnosed with ASD (Carter et al., Chawarska et al., Richler et al., Sutera et al., Watson et al.). The second group of 6 studies focuses exclusively on young siblings of children with ASD who do not themselves meet criteria for ASD, examining their early development and potential infant characteristics of the Broad Autism Phenotype (BAP).
Antecedents and very early signs of autism spectrum disorders
We open our special issue with a paper by Bryson et al., who offer a beautifully written description of 9 siblings of children with autism (SIBS-A) who were followed prospectively from age 6 months to age 36 months, and who were diagnosed with an ASD between 24 and 36 months. The clinical description is extremely rich and allowed the researchers to identify 2 subgroups of children. The first subgroup, which included 6 siblings, displayed a decrease in IQ (up to 41 points) - from average functioning to severe cognitive impairment - between 12 and 36 months. The second subgroup, comprising 3 siblings, continued to obtain average or near average scores from 12 to 36 months. Signs of autism were more striking in the first group but all of these affected siblings showed social and communicative impairments, atypical sensory and/or motor behaviours, irritability/distress, and dysregulation. Open questions remain as to whether the 2 groups manifest developmental pathways typical of autism with cognitive delay (1st group – low-functioning) and without such delay (2nd group – high-functioning), whether the sex differences that emerged in this small sample, in which the first group included mostly males and the second group only females, will be replicated with larger samples, and whether the temperamental profile that was revealed is associated with the emergence of ASD or precedes it.
In the next paper, Loh et al., working with some of the same infants included in the Bryson study, explored the motor stereotypies and movements of SIBS-A who developed autism. This study is unique because repetitive behaviours and postures were empirically described using a coding system that allows differentiation of these behaviours by body part, action and orientation. Stereotypic motor behaviour and postures were coded from videotapes of the participants during standardized testing at ages 12 and 18 months. There were few group differences in repetitive behaviors at 12 and 18 months, but SIBS-A who were later diagnosed with autism waved their arms more frequently than the comparison group at both ages and at 18 months more often covered their ears with their hands. A vital diagnostic issue is embedded in this paper in that the authors employed both a clinical diagnosis and a research one. The clinical diagnoses used DSM-IV-TR criteria, based on all available data (ADOS, ADI-R, assessments of cognition, language and daily living skills). The more stringent research diagnoses were based only on the ADI-R, ADOS, and DSM-IV-TR criteria. The findings changed as a function of type of diagnosis, with the significant difference in arm waving at 18 months no longer significant once research criteria were applied.
In the next paper, Sullivan et al. examined joint attention skills in 51 SIBS-A at ages 14 and 24 months as a function of outcome diagnosis at age 30/36 months. Outcome diagnosis was based on the 30/36 month ADOS and clinical judgment. The diagnosis of autism was assigned for 13 SIBS-A and the diagnosis of PDD-NOS for 3 SIBS-A. Eight additional SIBS-A were diagnosed with the BAP based on a language delay (1.25 standard deviations or more below the mean) or on a clinical judgement of social/behavioural/communication impairments. The remaining 27 SIBS-A were judged to be developing well, and assigned to the non-BAP group. Results indicated that SIBS-A later diagnosed with autism and PDD-NOS performed less well on some of the joint attention tasks. On most measures, SIBS-A later diagnosed with autism/PDD-NOS or with the BAP were indistinguishable from each other, and performed significantly worse than the non-BAP SIBS-A (i.e., who were well developing at ages 14 and 24 months). Joint attention skills at age 14 months predicted both language ability and the outcome diagnosis of ASD (autism and PDD-NOS as one group) and were quite stable at 24 months for the great majority of SIBS-A who were developing well, but only for about 50% of those diagnosed with ASD and the BAP. Together these three papers suggest that SIBS-A who later develop autism manifest risk signs related to communication, social behaviour and perhaps repetitive and stereotyped behaviours, all of which are impaired in autism, as early as 12-14 months of age.
The next three papers (Chawarska et al., Richler et al., Watson et al.) employed parental reports and offer valuable information about early parental concerns, risks associated with ASD, and the manifestation of restrictive and repetitive behaviours in young children. Watson et al. collected retrospective parental reports using a newly developed measure, the First Year Inventory (FYI). The FYI is a questionnaire designed to assess risk for ASD among 12 month old infants. In this study, as part of the validation of this new and exciting instrument, parents of 38 children with an ASD, 15 children with a non-spectrum developmental delay , and 40 children with typical development were asked to retrospectively complete the FYI regarding their child when s/he was 12 months of age. Results indicated that parents of children with an ASD endorsed significantly more items indicating atypical behaviour on the FYI than parents of children with a non-spectrum delay and parents of typically developing children. Children with ASD were rated higher, indicating greater impairment, than children in both comparison groups on the social orienting and receptive communication cluster, the social affective engagement cluster, and the reactivity cluster, suggesting that these behaviours may be helpful in distinguishing ASD and non-spectrum delays at 12 months. Children with ASD and non-spectrum delays were rated higher than typically developing children on the imitation cluster, expressive communication cluster, sensory processing cluster and repetitive play and behaviour cluster, suggesting that these behaviors are not specific to ASD at 12 months. There were no group differences for the regulatory patterns cluster.
Within the ASD group, parents rated boys higher (more impaired) than girls. When a cut-off score of 15 was used for ASD risk, 92% (35/38) of the children with autism, 80% (12/15) of the children with non-spectrum delays and 0 of the 40 typically developing children were identified by the FYI. When the cut-off score was raised to 22, 71% (27/38) of the children with autism, 40% (6/15) of the children with non-spectrum delays and again 0 of the 40 typically developing children were identified. Interestingly, risk scores were not correlated with age of diagnosis or age at first parental concern. Finally, the risk score at 12 months for children who experienced regression was significantly lower than the risk score for children with no regression, suggesting that early development was more typical for children with a regression. due to the fact that the regression occurred after 12 months of age.
Next, Chawarska and colleagues, also working with young children with ASD and their parents, explored the important question of the age at which parents recognize that development has gone awry. The findings of this study are that parents of children diagnosed with both Autistic Disorder and PDD-NOS report, on average, first recognition of developmental abnormality at about 14-15 months. Several patterns were evident, however, with some parents reporting earlier signs (e.g., before 11 months) and others recognizing problems between 11 – 17 months, or after 17 months. The most frequent concerns were in the domains of language development and social relatedness. Parents of children diagnosed with autism reported more early medical problems than parents of children diagnosed with PDD-NOS, whereas the latter group of parents reported more non-specific problems such as sleeping and eating difficulties. Parents of children with autism were more likely than parents of children with PDD-NOS to report loss of skills (e.g., regression) in their children. The autism and PDD-NOS groups did not differ on measures of cognition, language, daily living skills, and clinical symptoms. Interestingly, parents who expressed concerns arising between the ages of 11-18 months were as likely to have children later diagnosed with autism as with PDD-NOS, whereas both very early concerns (e.g., before the age of 11 months) and later concerns (e.g., after the age of 18 months) were associated with a diagnosis of autism more than PDD-NOS. This paper highlights both the similarities and differences in the reported early developmental trajectories of children later diagnosed with autism or PDD-NOS. This paper also highlights trajectories of onset that have not been well described by previous research, a point to which we will return below.
In the next paper, Richler et al. examined parental reports of the prevalence and severity of restricted and repetitive behaviours. Despite being a core domain of symptoms in autism, these behaviors have been much less researched than the social and communication difficulties of autism. Parents of 165 young children with ASD (117 with autism, 48 with PDD-NOS), 49 children with non-spectrum developmental delays and 65 children with typical development were interviewed using the ADI-R. Extending the report by Chawarska et al., no significant differences emerged between children diagnosed with autism and PDD-NOS, suggesting that repetitive and restricted behaviours, as reported by parents at age 2 years, do not assist in predicting which autism spectrum diagnosis the child will receive later on. Given the lack of significant findings between autism and PDD-NOS, these two groups were combined into one ASD group in all subsequent analyses. Items pertaining to restricted and repetitive behaviours were divided into a repetitive sensorimotor factor and an insistence on sameness factor. Children with ASD were found to have a higher prevalence of repetitive sensorimotor behaviours compared to children with non-spectrum DD and children with typical development. Insistence on sameness behaviours did not differ among the three groups. This suggests that early development of repetitive sensorimotor behaviours may be a marker for ASD, but insistence on sameness is probably not predictive.
Carter and her colleagues examined sex differences in very young children with autism between the ages of 18-33 months. Their findings indicate that boys scored higher than girls on measures of language and gross motor behaviour, whereas girls scored higher than boys on measures of visual reception. Boys were also rated by their parents as having more advanced social development than girls. Interestingly, girls and boys did not differ on clinical symptoms, although a trend emerged for girls to score worse on the communication domain as assessed both by the Vineland and the ADOS. These findings challenge our knowledge from typical development that girls, as a group, usually demonstrate better language abilities whereas boys, as a group, often display higher visual-spatial abilities. The question of whether girls are more severely affected, and if so, because of a higher threshold or dose of genetic vulnerability, remains open.
We end this group of papers dealing with the earliest phenotype of ASD with a fascinating paper on a group of 4 year olds with optimal outcome. In spite of the reported stability of early ASD diagnoses over time (Eaves & Ho, 2004; Lord, 1995; Moore & Goodson, 2003, Stone et al., 1999) we know that some children do improve and lose their diagnoses (Sigman & Ruskin, 1999). Sutera et al. studied 13 children who met criteria for an ASD at age 2 years but who, by the age of 4 years, no longer met the criteria and achieved average cognitive, adaptive living, and language scores. Children with an initial diagnosis of PDD-NOS were significantly more likely to move off the spectrum than children with an initial diagnosis of autism (39% versus 11% respectively). Interestingly, there were very few other differences between children who moved off the spectrum and those who didn't. When all the measures collected in the study were used to predict who would maintain the ASD diagnosis and who would not, only 3 of the children who moved off the spectrum were correctly classified. Thus, this study continues to challenge us as clinicians and researchers and demonstrate the need for further investigation of the characteristics that are, and are not, associated with stability of diagnosis.
Developmental milestones and trajectories of young siblings of children with ASD and their association with the broad autism phenotype
Whereas the previous group of papers focused on young children who had received ASD diagnoses (some of whom were younger siblings), this section concentrates on younger siblings of children with autism who do not have a diagnosis (either because they are too young to determine outcome or are old enough but do not meet diagnostic criteria). Many of these papers explicitly examine infant features of the broader autism phenotype. As long as we do not have stable outcome diagnoses, however, we cannot be sure that group differences will remain consistent once the siblings are further divided based on outcome. Therefore, the findings of some of the papers may change with time.
We open this section with a paper by Merin et al., who examined the affective displays and visual fixation patterns of 6-month-old SIBS-A and SIBS-TD during the Still Face procedure. Using sophisticated eye tracking procedures, these researchers found a subgroup of SIBS-A who were significantly more prone to gaze predominantly at the mouth -- 10 of the 11 infants characterized by this pattern were SIBS-A. This finding was striking given that SIBS-A and SIBS-TD did not differ with respect to affective displays (smiling and negative affect), total amount of fixation time, fixation directed at the face versus other areas, or fixation directed at individual facial features. The outcome of the 11 children who looked predominantly at the mouth is not yet known, so whether this finding is an early predictor of ASD or an endophenotypic marker is uncertain.
Cassel et al. also examined the social-communicative abilities of young SIBS-A. At age 6 months , similar to Merin et al., they administered the Still Face procedure and examined the affective displays (smiling, crying, and neutral expressions) of SIBS-A. Unlike Merin et al., who found no group differences in affective displays, Cassell et al. report that SIBS-A smiled less than matched typically developing infants, though similar to Merin et al., no differences emerged for crying and neutral expressions. These infants were retested at ages 8-18 months using the Early Social Communication Scales (ESCS, Mundy, Hogan, & Doehring, 1996) and found to initiate and respond to fewer joint attentions bids, as well as to initiate fewer high level behaviour regulation gestures. No associations were found among the affective measures during the Still face procedure at 6 months and the ESCS measures at 18 months.
Presmanes et al. also examined nonverbal communication and joint attention skills of SIBS-A and SIBS-TD between the ages of 12-23 months. An elegant procedure was used that examined ten different types of attention-specifying prompts, including both verbal and nonverbal cues and their combination with novel stimuli and object labels. SIBS-A performed significantly less well than SIBS-TD across the 10 prompts; this significant finding remained stable even when controlling for the trials in which the children did not look at any target. Responding to joint attention was especially difficult for SIBS-A when the prompts involved gaze shifts accompanied by directing verbalizations. Furthermore, responding to joint attention was correlated with later language and social communication in the SIBS-A group. It is worth noting that SIBS-A did not show difficulties in disengaging attention in this study, which have been reported for younger SIBS-A who developed autism in a previous paper (Zwaigenbaum, et al., 2005).
Toth and colleagues also examined nonverbal communication skills, as well as cognition, imitation, play, and language abilities, among 42 SIBS-A and 20 typically developing children between the ages of 18-27 months. Significantly more SIBS-A scored below average in overall IQ and expressive and receptive language compared to matched typically developing children. SIBS-A also achieved lower scores on parent report measures of communication, symbolic behaviour, and adaptive skills. There were no group differences in imitation and play. Examination of developmental histories revealed that SIBS-A were reported to have more social difficulties (first apparent at 13-15 months), sensory behaviours (at 10-24 months), and repetitive behaviours (at 22-24 months) than typically developing children.
The final two papers in this special section describe the developmental trajectories of SIBS-A (Gamliel et al., Iverson & Wozniak). In a detailed account of vocal and motor development, employing monthly visits from 5 to 14 months, with an outcome assessment at age 18 months, Iverson and Wozniak report that more SIBS-A were delayed relative to typically developing infants in the onset of important milestones such as sitting, babbling, showing, and first words. Furthermore, on average, the posture bouts of SIBS-A were significantly shorter than those of the comparison group, suggesting that posture was less stable. Finally, at 18 months, 9 of the 14 SIBS-A revealed a clinically significant delay in either receptive and/or expressive language. This study is unique in its use of journals and audio-tapes collected by parents at home on a regular basis coupled with experimental observation and testing.
Finally, Gamliel et al. report on their longitudinal findings from age 4 to 54 months in SIBS-A and SIBS-TD. This study is unique in both its longitudinal perspective and its methodology, matching the groups carefully at age 4 months on measures of development, temperament, and familial characteristics such as parental age, education, birth order, and socio-economic status. The findings of this study indicate that most SIBS-A were functioning well in terms of cognition and language at age 4½. However, two groups of SIBS-A with delays were identified, one at age 14 months and another at age 24 months. Only this latter group continued to present language delays at age 54 months. This is reassuring news for parents of a child with ASD and a new baby, although it does not preclude the need for careful monitoring of young siblings.
In this section we outline some of the major issues relating to the study of high-risk samples and young children with ASD presented by papers in this volume. Some of these issues, as well as others, have also been discussed in a recent paper by Zwaigenbaum et al. (2006).
Convergence across methodologies
The 14 studies in this special section fall into three methodological types: prospective studies of high risk samples, prospective follow-along studies of very young children just diagnosed with autism, and retrospective investigations using parental reports of the early characteristics of children with autism. Each approach has strengths and weaknesses. Parent report (e.g., Chawarska et al., Richler et al., Watson et al.) is an efficient method of collecting early history information. It may, however, be biased by knowledge of the child's eventual diagnosis, poor recall, and parental under- or over-sensitivity to developmental differences. Prospective studies of toddlers newly diagnosed with autism (Carter et al., Sutera et al., this issue) provide the opportunity to explore manifestations apparent from as early as 18 months of life, yet even these methods do not provide information about infancy. Another prospective strategy involves the study of infant siblings of children with ASD (Bryson et al., Cassel et al., Gamliel et al., Iverson & Wozniak, Loh et al., Merin et al., Presmanes et al., Sullivan et al., Toth et al.) in which the development of infants at risk for autism is followed from closely after birth through the window of autism susceptibility. There are challenges encountered with this method as well. The principal problem is that a very large sample is required in order to find several children who yield informative early data.
Despite the potential limitations of each methodology, the different strategies for collecting early developmental information have yielded relatively consistent results. As detailed above, several papers in this special section suggest that early differences in joint attention, shared affect, verbal communication, and repetitive behavior are common in infants and toddlers later diagnosed with ASD. Similarly, several studies found early social-communicative delays in younger siblings of children with ASD, even those who did not later go on to be diagnosed on the spectrum. Convergent data across several methodological approaches strengthens our confidence in the results.
Small samples and null results
Most of the papers in this special section report not only traditional tests of statistical significance, but also effect sizes, metrics of the magnitude of group differences that are independent of sample size. This is particularly important for studies, such as most of the ones included in this issue, in which the samples are small (e.g., subgroups of infant siblings who later meet criteria for autism or ASD). Effect size indices may reveal meaningful group differences that have not attained statistical significance due to low power, secondary to small sample size. In addition, and perhaps even more importantly, effect sizes help us confirm that a lack of statistically significant differences is due to small differences between groups, rather than simply an artifact of low power. The burden of proof is actually greater when the finding of interest is one of null results. So, for example, in the paper in this issue by Gamliel et al., which presents longitudinal data from 4 to 54 months for infant siblings of children with autism, the finding that most siblings are well-functioning at 54 months is supported both by lack of statistically significant differences between the groups and by the presence of small effect sizes (i.e., large group overlap). Since no other infant sibling studies have been underway as long as that by Gamliel et al., their findings of generally intact cognitive and language development at age 4½ provide important data to the field. Yet in some cases, non-significant group differences are accompanied by a large effect size suggesting that the non-significant group difference was most likely due to small sample sizes and lack of power. Therefore we recommend that both approaches be employed in future studies. We can be more confident about our findings when both criteria coincide.
Onset and regression Another central issue related to the very early phenotype of autism addressed by multiple papers in this issue has to do with onset or when precisely in development the features of autism emerge. Studies using both prospective and retrospective methods are relevant to the theme of onset. The paper by Chawarska et al. provides a thoughtful summary of the previous literature on this topic and a new look at how parental age of recognition is related to both onset classifications and later outcome. One interesting suggestion made by these authors is that not all “late emerging autism” is due to developmental skill loss or regression. An additional onset pattern, in which parents do not note atypicalities in their child's early development, may be due to failures to use intact dyadic social reciprocity skills (e.g., mutual gaze, social smiling) in a more sophisticated manner in the second year of life, to support the typical maturational processes of speech acquisition, intentional communication, and triadic social interactions. In such cases, the early intact behaviours fade away because they are not reinforced by the natural predisposition to seek and communicate with others. What might seem like a loss of skills is simply a failure to progress and transform the basic skills into their more developmentally advanced versions. Klin et al. (2004) have used the term pseudo-regression to describe this pattern and it has also been referred to as developmental stagnation (Siperstein & Volkmar, 2004) and developmental plateau (Hansen, Ozonoff, et al., under review).
The fascinating case descriptions from the paper by Bryson and colleagues in this issue also describe several children whose symptoms are not present early on (at their 6 and 12 month visits), but emerge slowly over time. Not a single child displayed marked limitations in social reciprocity at 6 months. All nine infants were described as interested in social interactions, responsive to others, demonstrating sustained eye contact and social smiles. Paradoxically, most of the children did not experience an explicit loss of previously acquired skills that would meet established definitions of regression (e.g., such as the ADI-R definition), providing additional evidence for another type of later onset pattern. Two previously published case studies (Dawson et al., 2000; Klin et al., 2004) report on children who were noted to be symptomatic by the first birthday, but who presented with mostly intact social behaviour in the first 6-12 months and did not experience a clear regression as symptoms began to emerge. Thus, the prototype first described by Kanner (1943) that “extreme aloneness [is present] from the very beginning of life” (p. 248) may not in fact be very common. The papers in this special section raise new questions about onset and suggest that existing definitions of onset patterns will need to undergo further development as new data emerges from future studies, particularly those using prospective samples, which will be less affected by potential reporting and recall biases inherent in retrospective studies.
Definitions of the BAP in infancy
Another issue raised by multiple papers in this special section is the broad autism phenotype. This term has been used to describe subsyndromal differences that are qualitatively similar to, but milder than, the features of autism, including difficulties in social engagement and reciprocity, language and communication, and repetitive behaviour. Previous studies report features of the BAP in 15-45% of family members of people with autism (Bailey et al., 1998). Past research on the BAP focused exclusively on older children and adults. The current set of papers includes several that explicitly examine infant manifestations of the BAP (Cassel et al; Gamliel et al.; Iverson & Wozniak; Merin et al.; Presmanes et al; Sullivan et al.; Toth et al.). Since the BAP in adults and older children echoes the triad of symptoms seen in autism, it is especially interesting to find that this pattern also holds true across development; that is, younger siblings of children with autism display difficulties in similar domains as children diagnosed with autism. Speech and language delays (Gamliel et al.; Toth et al.), joint attention delays ( Presmanes et al; Sullivan et al.; Toth et al.), reduced affective expression ( Cassel et al), gaze to the eyes during reciprocal social interaction (Merin et al.), and motor delays (Iverson & Wozniak) were all reported in younger siblings of children with autism in papers in this special section. Given the current early stage of this research, however, it is crucial to entertain the possibility that some characteristics of the broad autism phenotype may vary across development, with some delays being transient while others are more lasting. Clinically, the uncertainty about the stability of these difficulties is important to convey to parents, so as not to unnecessarily alarm families.
This work on the infant BAP may be important for future genetic studies. Autism is thought to have a multifactorial, polygenic aetiology and research suggests that multiple genes may confer susceptibility to different traits (Pickles et al., 1995; Wassink et al., 2001). An endophenotype is a measurable pattern that is intermediate between a disease and a distal genotype that confers vulnerability to the disease. Endophenotypes may represent the inheritance of a gene, or subset of genes, related to the disorder and are found in both affected individuals and in unaffected family members who carry the overlapping genotype (Gottesman & Gould, 2003). The presence of a broader autism phenotype suggests that what is inherited is more expansive than autism as it is currently defined. As we get better at determining who is “affected” in family and genetic studies, we should get closer to identifying candidate genes that confer genetic susceptibility (Piven, 2001).
An issue important for the field to grapple with is how to define the BAP in infancy. It is a fuzzy, globally defined concept even in older children and adults, but particularly in infancy there are no accepted or agreed upon definitions. Some papers in this volume have used a priori definitions that are reasonable downward extensions of the criteria used for older children and adults (e.g., performance of one or two standard deviations from the typical mean on measures of social engagement, communication, or repetitive behaviour). Another approach is to develop definitions empirically, once outcome in later childhood is known. Performance on tasks early in development that distinguish between children who go on to demonstrate the BAP, as it is measured in older children (e.g., using the Social Reciprocity Scale or the Family History Interview; Bolton et al., 1994; Constantino et al., 2006), and those who do not can be used to develop new, infant-appropriate metrics of the BAP in infancy.
Recurrence rates of ASD and other impairments
One of the most intriguing questions that is of concern to both parents and professionals is that of the recurrence rate of ASD, as well as rates of other delays (e.g., BAP characteristics). Unfortunately, the experimental designs and methodologies employed in this group of studies cannot yet address this question. Although some authors report on rates of ASD and other delays in their groups of younger siblings, it is crucial to realize that most are samples of convenience and thus inappropriate to use to answer epidemiological questions about recurrence. Parents may enroll in a study only after becoming concerned about some aspect of development or may participate to confirm that their younger child is developing just fine. Furthermore, in some studies in this issue that are still in progress, no outcome data is available regarding the stability of findings, complicating even further the ability to make any inferences about recurrence and affectedness rates. For example, in the Gamliel et al. study, some infants were characterized as delayed in language at 14 months, whereas others only at 24 months. The data indicated that the delay was transient for the first group, but stable up to 54 months for the second group. Since the children are developing and development is uneven at times, we need to wait patiently until more data is available to determine which findings are transient and which are robust. Several papers in this special section suggest potential markers for later ASD diagnoses and these need to have sensitivity and specificity determined in larger, preferably epidemiological, samples. Thus, it is unclear if recurrence rates will be lower or higher once stringent epidemiological studies are carried out. As responsible professionals, our primary goal is to identify families and children who may benefit from help and provide intervention services where needed. Effective interventions may hopefully alter the natural course of development that has gone awry, thus making inferences regarding recurrence rates even less accurate.
Age of diagnosis
Detecting autism at the individual level before the age of 2 years may be particularly difficult for prospective samples. It is possible that the presentation of children who are referred by their pediatricians or parents for suspected autism is substantially more clear-cut (with obvious delays and deviances characteristic of autism) than the variability seen in prospective samples. This should be studied in future research.
In this kind of work, it is very important that professionals conducting evaluations are blind to group membership so that prior expectations do not influence the process. This is also crucial because the ADOS, one of the most widely used diagnostic instruments, was standardized with children with ASD and other delays and not necessarily with typically developing children, some of whom may score close to cut-off criteria due to difficulties other than ASD (e.g., very timid, reserved and anxious young children).
We must also think about (and perhaps contrast) the earliest age versus the optimal age at which a diagnosis can be made, with associated implications for identification, labelling, and referral for intervention. This issue is relevant to making both ASD and other diagnoses. Some of the papers in this special issue include information regarding group differences whereas others report on clinical counts – that is on how many children, given a certain cut-off criteria, meet these criteria (e.g., score two standard deviations below the mean on any given measure). By counting clinical cases, we are actually identifying and labelling these children, before we may really know whether our criteria are stable and meaningful (see above section on defining the BAP in young children). Whereas the group comparison approach only informs us about group differences and may be strongly affected by extreme cases, it avoids the issue of labelling. Labelling and diagnosing is important for service providers as it is likely that only those children who are identified and labelled would be eligible to receive services. In the work reported with younger siblings, it is difficult to determine the youngest age at which infants should be identified as exhibiting worrisome conditions and be diagnosed so that intervention can be offered. The earliest possible age at which we may be able to diagnose or identify children may not coincide with the optimal age, as the optimal age may be younger or older depending on specific value systems. The studies reported by Sutera et al. and Gamliel et al. clearly point out that some conditions are transient. Although the children in the Sutera et al. paper received intensive behavioural treatment, most of the children in the Gamliel et al. study did not. It may be that professionals will need to adhere to different thresholds for different groups and/or different conditions, using clinical judgement rather than rigid cutoffs to decide when children should be labelled and referred for intervention. The optimal age of diagnosis would be that which will maximize sensitivity, specificity, and positive and negative predictive value. Poor sensitivity and a high rate of false negatives are worrisome because some children would be undiagnosed and untreated. Yet, poor specificity and a high rate of false positives would induce unnecessary worries, stress and anxiety, and might be especially detrimental to families who already have one child with an ASD.
Conclusions and future directions
As is often true with cutting edge research, it raises as many questions as it answers and that is the case with the papers in this special section. This body of work makes some things clearer. For example, these studies collectively show, among other things, that early differences in joint attention, shared affect, verbal communication, and repetitive behaviors are common in infants and toddlers later diagnosed with ASD, that autism is not always present (or at least clinically evident) “at birth” as once thought, and that younger siblings of children with autism are at risk of multiple adverse developmental outcomes. We are left with many other questions, however. How do we define the BAP in infancy? Are the impairments and delays that we see in young siblings of children with autism specific to this high risk group or are they shared with younger siblings of children with other non-spectrum delays? Which comparison groups should we study to determine which phenomena are specific and unique to SIBS-A? What are different trajectories of onset for autism? How early can we diagnose autism? How do we treat infants or young toddlers who appear to be affected? Do children with BAP signs require treatment? What is the sibling recurrence rate for the various autism spectrum disorders and the BAP?
Recent papers have highlighted the ethical issues inherent in this kind of work (Chen, Miller & Rosenstein, 2003; McMahon, Baty & Botkin, 2006; Zwaigenbaum et al., 2006) and indeed many of the questions raised by the papers in this special section fall in the ethical domain. We will highlight a few here. A major issue that must be wrestled with is how and when to raise concerns about very young children, when a diagnosis is not yet clear and there may be few resources available for intervention. One purpose of the drive for earlier identification is that treatments delivered at very young ages, when the brain is most plastic, may ultimately lessen or prevent the lifelong challenges associated with autism. At the present time, however, there are no established treatments for very young children who may be on the autism spectrum. There is an urgent need for the development of such interventions and study of their efficacy and effectiveness. Although it challenges the design of studies on onset and may ultimately reduce group differences, it is an ethical imperative to make referrals for treatment when clear developmental difficulties are identified.
Based on the notion that a genetic predisposition may be essential but not sufficient for the expression of some phenotypes, as intervention and perhaps preventions programs are established and implemented, we may learn more about the interaction between genes and environment. For some siblings and other young children at risk for ASD or the BAP, the genetic predisposition may be strong enough so that even with the most optimal environment and prevention/intervention programs, these children will eventually meet criteria for ASD or the BAP. For other children, the genetic predisposition may be somewhat weaker and more receptive to certain environmental influences, including prevention/intervention programs. The magnitude of the genetic predisposition, as well as that of the responsiveness to environmental influences, may be associated with various variables such as the number of children already diagnosed with ASD in the family, gender of the child (and, where applicable, also of the older sibling with autism), level of functioning, and parent-child relations.
Another exigency for the field is the development of valid and reliable biomarkers that may permit identification at or even before birth, long before behavioural signs become evident. Beyond generating information about who may be at increased risk, it is incumbent upon the field to determine the clinical validity of a biomarker, that is, its ability to predict the clinical phenotype (McMahon et al., 2006). The wide spectrum of affectedness, ability, and disability seen across individuals and even within families makes it clear that such prediction will be very challenging indeed.
Another future direction for the field that is clearly motivated by the corpus of research in this issue is more microscopic study of onset. While it was once thought that autism was present “from the very beginning of life” (Kanner, 1943, p. 248), the studies in this issue contest that claim. Signs of autism are certainly present far earlier than the diagnosis is currently made, yet they emerge over time and are not always evident even to the expert clinical eye before 12 months. Future studies should incorporate designs that sample development and behaviour very frequently from 6 to 18 months, in hopes of tracking the subtle and insidious changes that seem to occur during this time period. Large samples will likely be necessary and therefore more efforts like those of the Baby Sibling Research Consortium, which call for collaborative multi-site large-scale studies, will be fruitful.
We have come a long way in the last 5-10 years, from knowing very little about the earliest phenotype of autism, to having so many research groups studying early identification and phenotyping that all the work could not be collected in one issue. While this issue may raise more questions than it answers, we hope that it gets us a bit closer to providing the immediate clinical care that will ultimately lessen or even prevent at least some, if not all of the disabilities associated with autism.
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