What are the surprises in this literature? The most surprising finding thus far involves the lack of behavioral markers of ASD at 6 months thus far identified. Given the robust social nature of typical 6 month olds, and the profound social impairment seen in toddlers with autism, the mindset of most of the investigators going into these studies was not whether
they would find behavioral differences, but rather what
they would be. The lack of overt behavioral identifiers at 6 months is changing our ideas about the course of autism and our ideas about the continuity of social behavior across infancy. Furthermore, the earliest differences found are subtle, as in the area of repetitive behaviors, where differences involve only a very few behaviors or a small difference in means. Lack of differentiating symptoms at 6 months suggests a discontinuity to social development, with early sociability supported by different underlying mechanisms than toddler sociability (cf with Kagan, 2008
). Certainly the number of studies and number of measures used thus far is small, and the use of other risk markers may reveal clearer differences. However, even if clear differences are found that predict to diagnosis, using eye tracking, ERP, microanalysis of videos, or other very detailed methods (and I for one assume that we will find these), it will not diminish the surprise of looking at these 6 month videos and observing the smiling, social, responsive infants who will later develop autism.
Does the lack of early evidence suggest environmental causation? On the contrary, the rate of autism and related difficulties in these siblings confirms for us the importance of genetic contributors to the disorder. We assume that the biology of autism is in place at 6 months, even though the behavior of autism is not. However, reliable markers of autism in early infancy may end up coming from biology rather than behavior. We may not find a litmus test for autism, even in biology. The best we may be able to do is to settle for odds ratios and severity of risk indicators.
The second surprise involves the variety of course and timing of the onset of the behavioral autism phenotype. The patterns emerging from these studies do not fit either the early onset or the regressive patterns we have come to expect – points thoroughly discussed in recent papers by Landa & Garrett-Mayer (2006)
and Ozonoff et al., (in press). The patterns instead involve slower or faster mounting of symptoms, more or less deceleration of general development, earlier or later onset of social difficulties – differences that seem more continuous than dichotomous. It is fascinating in these case studies to read that not only the core symptoms like joint attention deficits, repetitive behaviors, and language delays appear at 12 months and grow more severe over time, but even what were previously considered secondary symptoms – irritability, sensory responsivity, activity level, and poor gross motor development, are on board, and in some cases appear well before
the social problems! These findings do not support the view that autism is primarily a social-communicative disorder and instead suggest that autism disrupts multiple aspects of development rather simultaneously. Children’s developmental rates are decelerating markedly in a 12 month time period, with IQs dropping from average to below 50 for some children. There is no other developmental disorder with this kind of course (the CDD group stands out for the fastest, latest onset into the same symptom set). The social-communicative symptoms and the unusual onset appear to distinguish these children from others with multiple delays, but to suggest that autism is primarily about social communication does not fit these data well. Perhaps as a colleague recently suggested (Cameron Carter, 2007, personal communication), onset in autism will be found to resemble the pattern (though not of course the timing) seen in schizophrenia, with a modal point of onset and a rather bell shaped curve extending into earlier and later periods, perhaps reflecting random variation in genetic timing rather than environmental triggers.
A third important point – not a surprise, but a reminder – is the extreme range of severity in each of the symptoms seen in affected toddlers. Even in infancy, each of the core symptoms, and developmental rate, may be severely affected or may be much more mildly affected. It is the pattern of symptoms that defines autism, with a wide range of severity, and screeners and diagnostic measures that are sensitive to autism in less impaired toddlers, who may not show deficits in joint attention, imitation, expressive language, and symbolic play, are badly needed. These data on the variability of onset timing and the range of symptoms have significant ramifications for pediatric autism screening efforts, which will need to occur repeatedly until 36 months of age, using screeners that are sensitive to both more and less severely affected toddlers, if we are to identify most children with ASD in the preschool period.
Discrepancies exist throughout these studies. Are there abnormalities in the still face response or are there not? Do high risk infants who do not develop ASD show developmental delays at 12 months or not? Are there imitation differences in these siblings or not? Do these infants demonstrate difficulties with response to joint attention, or do they not? Many of these discrepancies likely currently exist because the methods and subjects differ across studies. The field needs a common approach to categorization of high risk subgroups. One would expect that a group of high risk infants that includes infants who will develop ASD will show more deficits, and more variability, than a group of high risk infants who do not develop ASD. Differences in coding constructs and practices will result in different findings. Rating duration of eye contact using eye tracking technology will provide different data than rating duration of gaze from video. This is a very young field, and investigators are currently developing original experiments and methods. Hopefully, the next wave of studies will provide real replications involving a duplication of methods. Additionally, as studies are published, convergences across studies using slightly different methods will provide needed replications.
What is the nature of the broader familial phenotype in infancy? While the broader, or familial phenotype, in ASD as it occurs in older children and adults has been well characterized by others (e.g. Dawson, Webb, Schellenberg, Dager, Friedman, Aylward, and Richards, 2002
; Skuse, 2001
), data on infants are only beginning to emerge. The necessary design, as illustrated in the Toth et al. 2007
paper, involves a comparison of high risk infants who do not develop ASD to low risk infants, and has been carried out by very few researchers thus far. From the available data, the high risk infants who do not develop ASD do not demonstrate the range of symptoms involving temperamental problems, motor problems, and repetitive behaviors that the ASD infants show. Several studies have demonstrated atypicalities in visual processing of both social and nonsocial stimuli (Elssabagh et al, in press
; Merin et al, 2006; McCleery et al, 2007
; Elsabbagh et al, 2009
). There is also replicated evidence of significant difference in some aspects of social communication from low risk groups, though not at the impaired level of the infants who develop ASD. We have no information on whether infant siblings without ASD who show early atypicalities will show the known patterns associated with the BAP at school age or later. Differing severities of affectedness in the BP are likely to represent points on a continuum from typical to autistic development, as occurs in older groups (Constantino, & Todd, 2003
). We await data from larger studies to provide a clearer picture of the onset, course, and profiles of the high risk infants who do not develop ASD. The data and cautions from Gamliel and colleagues (2007)
are particularly relevant here, though the study is quite small, and thus far not replicated. If delays resolve by 54 months in some untreated high risk children who did not have ASD, what do the delays mean? If they resolve, should we be routinely recommending treatment when delays are found in infants? And, if so, what level of severity should be the deciding point for diagnosis and/or referral? Does this apparent plasticity in the nonASD high risk sibs speak to the level of plasticity in infants who develop ASD? Will treatment be more effective if begun earlier? The recovery seen in that small group of high risk infants with delays but without ASD is one of the most provocative findings thus far in the infant sibling studies (see Elssabagh and Johnson, 2007
for further discussion on this issue).
The last point concerns the importance of “unpacking” a group difference. For Presmanes et al. (2007) Nadig et al. (2007)
, and Young et al. (in press)
, among others, identifying a group difference is only a very early step in the analytic approach. Once a difference was detected, the researchers in these studies used the follow-up diagnostic data and the other measures to determine the nature of the group difference, often with surprising results. Who would have thought that infants who look more at mouths than faces would have superior language development? Who would have thought that response to name reflects social initiative, as opposed to receptive language? What does it mean if a group difference involving poorer performance in the high risk group does not differentially affect the children who will develop ASD?
These investigators have made us acknowledge that a difference between high risk and low risk infants is not necessarily a red flag for autism risk or any other risk. It highlights a second point as well, that behaviors that connote abnormality in a later developmental period (e.g. increased gaze to mouth versus eyes during social interactions) do not necessarily connote abnormality in an earlier developmental period. We must be quite careful to examine the meaning of behaviors anew when we take paradigms and findings from one developmental period to another. There is so much theorizing in autism, so many “just so” stories, that we are grateful to researchers who see that the task involves not just defining group differences, but rather chipping away to understand them. This approach to the data is encouraged for the field as a whole.
The questions initially driving these studies have led to some answers, and to new questions, questions that are now driving the second wave of such studies. The initial question – predicting autism risk in infancy – is now being examined in many studies through more basic measures, like eye tracking and ERP. Longitudinal studies are needed to define the ongoing course of both those sibs who develop ASD and those who do not. Do those sibs with some early delays but no ASD go on to develop greater, or diminished, problems over time? Do the two early subgroups within ASD demonstrate different trajectories of development? Are the high risk sibs with delays but not ASD the same group who will demonstrate the familial autism phenotype in later childhood, adolescence, and adulthood? How many of them will eventually be diagnosed with ASD? Are the abnormal gross and fine motor skills, increasing repetitive behaviors, and increasing sensory responsivities related in these very young children? And, of course the over-riding question: what is occurring in the central nervous system of these children that accounts for the gradual onset of autism symptoms in the second year of life? And what can be done to stop the progression and reverse the downward course? These, and many other important questions, remain to be addressed in these complex and fascinating longitudinal studies of infants at risk of ASD.
In conclusion, it appears that autism is not a disorder that profoundly affects social development from the earliest months of life. Rather, it is a disorder involving symptoms across multiple domains with a gradual onset that changes both ongoing developmental rate and established behavioral patterns across the first two to three years of life, and typically results in severe social-communication impairment.