Evaluation of the Diagnostic Stability of the Early Autism Spectrum Disorder Phenotype in the General Population Starting at 12 Months

Abstract

Importance: Universal early screening for autism spectrum disorder (ASD) in primary care is becoming increasingly common and is believed to be a pivotal step toward early treatment. However, the diagnostic stability of ASD in large cohorts from the general population, particularly in those younger than 18 months, is unknown. Changes in the phenotypic expression of ASD across early development compared with toddlers with other delays are also unknown.

Objectives: To examine the diagnostic stability of ASD in a large cohort of toddlers starting at 12 months of age and to compare this stability with that of toddlers with other disorders, such as developmental delay.

Design, setting, and participants: In this prospective cohort study performed from January 1, 2006, to December 31, 2018, a total of 2241 toddlers were referred from the general population through a universal screening program in primary care or community referral. Eligible toddlers received their first diagnostic evaluation between 12 and 36 months of age and had at least 1 subsequent evaluation.

Exposures: Diagnosis was denoted after each evaluation visit as ASD, ASD features, language delay, developmental delay, other developmental issue, typical sibling of an ASD proband, or typical development.

Main outcomes and measures: Diagnostic stability coefficients were calculated within 2-month age bands, and logistic regression models were used to explore the associations of sex, age, diagnosis at first visit, and interval between first and last diagnosis with stability. Toddlers with a non-ASD diagnosis at their first visit diagnosed with ASD at their last were designated as having late-identified ASD.

Results: Among the 1269 toddlers included in the study (918 [72.3%] male; median age at first evaluation, 17.6 months [interquartile range, 14.0-24.4 months]; median age at final evaluation, 36.2 months [interquartile range, 33.4-40.9 months]), the overall diagnostic stability for ASD was 0.84 (95% CI, 0.80-0.87), which was higher than any other diagnostic group. Only 7 toddlers (1.8%) initially considered to have ASD transitioned into a final diagnosis of typical development. Diagnostic stability of ASD within the youngest age band (12-13 months) was lowest at 0.50 (95% CI, 0.32-0.69) but increased to 0.79 by 14 months and 0.83 by 16 months (age bands of 12 vs 14 and 16 months; odds ratio, 4.25; 95% CI, 1.59-11.74). A total of 105 toddlers (23.8%) were not designated as having ASD at their first visit but were identified at a later visit.

Conclusions and relevance: The findings suggest that an ASD diagnosis becomes stable starting at 14 months of age and overall is more stable than other diagnostic categories, including language or developmental delay. After a toddler is identified as having ASD, there may be a low chance that he or she will test within typical levels at 3 years of age. This finding opens the opportunity to test the impact of very early-age treatment of ASD.

Figure 1.. Sample Characteristics

Distribution of key features associated with the study cohort, including the age (in months) that toddlers received their first comprehensive diagnostic evaluation (A), the number of toddlers who received 2, 3, or 4 or more diagnostic evaluations (B), the age (in months) that toddlers received their last diagnostic evaluation, and the interval (in months) between a toddler’s first and last diagnostic evaluation (D).

Figure 2.. Transition Table and Diagnostic Heat Maps

A, Summary of the proportion of toddlers from within the entire sample (N = 1269) who retained or moved to a different diagnostic group between their first and last diagnostic visits. Stability coefficients are denoted within each cell (coefficients are not adjusted for the age at first diagnosis; a high concordance with age-adjusted coefficients was observed) (eTable 4 in the Supplement gives coefficients adjusted for age at first diagnosis). To read the table, compare values across each row or vertically within each column. For example, of the 400 toddlers initially designated as having autism spectrum disorder (ASD), 336 retained this diagnosis at their last (final) diagnostic visit, yielding a diagnostic stability coefficient of 0.84, whereas 35 toddlers had ASD features but no longer met ASD criteria, 6 tested as developmentally delayed, 6 as language delayed, 10 had other developmental issues, and 7 were designated as typically developing with no residual symptoms. For transition tables with stability coefficients within 2-month age bands, see eFigure 4 in the Supplement. B, Changes in diagnosis across visits. Colors represent each diagnostic group and rings represent each diagnostic visit, with the smallest center ring representing the first visit. The left-most panel summarizes diagnostic changes for toddlers who received 2 diagnostic evaluations a mean of 15 months apart; the center represents toddlers who received 3 diagnostic evaluations a mean of 11 months apart; and the right-most panel represents toddlers who received 4 or more diagnostic evaluations a mean of 8 months apart. The heat map indicates that ASD was the most stable diagnostic category, and that toddlers initially suspected as having developmental delay (DD) or language delay (LD) frequently received a final diagnosis of ASD. TD indicates typical development.

Figure 3.. Diagnostic Stability Plots by Age at First Diagnosis

A, Plots show diagnostic stability per group across 2-month age intervals based on the age at first diagnostic evaluation. Age intervals with missing data points reflect an absence of toddlers who received their first diagnostic evaluation at that age. B-spline logistic regression line is shown; bands represent 95% CIs for the fit line. Overall stability was highest in toddlers initially designated as having autism spectrum disorder (ASD) or typical development as illustrated by the relatively tight CI bands, and the largely consistent stability coefficients within each age band. B, Diagnostic stability coefficients in the 4 age bins used in the logistic regression model across diagnostic groups. The lines represent 95% CIs. Coefficients were estimated based on within group logistic regression models. eFigure 5 and eFigure 6 in the Supplement give complementary analyses.

Figure 4.. Comparison of Clinical Features in Toddlers With Autism Spectrum Disorder (ASD) Stratified by Identification Age

Violin plots show differences in Autism Diagnostic Observation Schedule (ADOS) total scores (A), Mullen Expressive Language T scores (B), Vineland Adaptive Behavior Composite scores (C), and Mullen Receptive Language T scores (D) at the first diagnostic evaluation between toddlers with ASD identified at 12 to 18 months of age (early-age persistent ASD diagnosis), toddlers with ASD identified after 18 months (middle-age persistent ASD diagnosis), or toddlers not identified as having ASD at their first diagnostic visit (late-identified ASD). Black dots represent the mean. The width of the shape represents patient density, and the length illustrates the range of the scores. Data from 270 toddlers with typical development (TD) identified at their first diagnosis visit and retaining that diagnosis at their last visit are shown for comparison. Note that scores from the late-identified group were significantly different from toddlers with TD across all clinical domains, suggesting that symptoms were already present at the first diagnostic visit in a large fraction of late-identified ASD cases. Also note that 39 toddlers in the late-identified group (37%) did fall within the range of concern on the Autism Diagnostic Observation Schedule toddler module (cutoff score for concern using the few to no words algorithm = 10), however, were designated as non-ASD based on practitioner judgment, underscoring the challenges in differential diagnoses particularly at the youngest ages. Effect sizes are reported as Cohen d (95% CI). eFigure 3 in the Supplement gives an expanded figure that includes all diagnostic groups.