Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices.
OBJECTIVE
The identification of genomic signatures that aid early identification of individuals at risk for autism spectrum disorder (ASD) in the toddler period remains a major challenge because of the genetic and phenotypic heterogeneity of the disorder. Generally, ASD is not diagnosed before the fourth to fifth birthday.


OBJECTIVE
To apply a functional genomic approach to identify a biologically relevant signature with promising performance in the diagnostic classification of infants and toddlers with ASD.


METHODS
Proof-of-principle study of leukocyte RNA expression levels from 2 independent cohorts of children aged 1 to 4 years (142 discovery participants and 73 replication participants) using Illumina microarrays. Coexpression analysis of differentially expressed genes between Discovery ASD and control toddlers were used to define gene modules and eigengenes used in a diagnostic classification analysis. Independent validation of the classifier performance was tested on the replication cohort. Pathway enrichment and protein-protein interaction analyses were used to confirm biological relevance of the functional networks in the classifier. Participant recruitment occurred in general pediatric clinics and community settings. Male infants and toddlers (age range, 1-4 years) were enrolled in the study. Recruitment criteria followed the 1-Year Well-Baby Check-Up Approach. Diagnostic judgment followed DSM-IV-TR and Autism Diagnostic Observation Schedule criteria for autism. Participants with ASD were compared with control groups composed of typically developing toddlers as well as toddlers with global developmental or language delay.


METHODS
Logistic regression and receiver operating characteristic curve analysis were used in a classification test to establish the accuracy, specificity, and sensitivity of the module-based classifier.


RESULTS
Our signature of differentially coexpressed genes was enriched in translation and immune/inflammation functions and produced 83% accuracy. In an independent test with approximately half of the sample and a different microarray, the diagnostic classification of ASD vs control samples was 75% accurate. Consistent with its ASD specificity, our signature did not distinguish toddlers with global developmental or language delay from typically developing toddlers (62% accuracy).


CONCLUSIONS
This proof-of-principle study demonstrated that genomic biomarkers with very good sensitivity and specificity for boys with ASD in general pediatric settings can be identified. It also showed that a blood-based clinical test for at-risk male infants and toddlers could be refined and routinely implemented in pediatric diagnostic settings.
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Tiziano
T
Pramparo
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Karen
K
Pierce
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom3Department of Psychology, University of Cyprus, Nicosia, Cyprus4Center for Applied Neuroscience, University of Cyprus, Nicosia, Cyprus.
Michael V
MV
Lombardo
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Cynthia
C
Carter Barnes
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Steven
S
Marinero
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Clelia
C
Ahrens-Barbeau
Scripps Genomic Medicine and Scripps Translational Sciences Institute, La Jolla, California6Department of Pathology, University of California, San Diego, La Jolla.
Sarah S
SS
Murray
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Linda
L
Lopez
Department of Family and Preventive Medicine, University of California, San Diego, La Jolla8Department of Mathematics, University of California, San Diego, La Jolla.
Ronghui
R
Xu
UC San Diego Autism Center of Excellence, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla.
Eric
E
Courchesne
D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D042241:Early Diagnosis; D006801:Humans; D007109:Immunity / Q000235:genetics*; D007223:Infant; D007249:Inflammation / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis; D011237:Predictive Value of Tests; D060066:Protein Interaction Maps; D012313:RNA / Q000096:biosynthesis; D012680:Sensitivity and Specificity; D059467:Transcriptome / Q000235:genetics
D015415:Biomarkers; D012313:RNA