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The cost associated with incorporating standardized observational assessments and diagnostic interviews in large-scale epidemiologic studies of autism spectrum disorders (ASD) risk factors can be substantial. Streamlined approaches for confirming ASD case status would benefit these studies. We conducted a multi-site, cross-sectional criterion validity study in a convenience sample of 382 three-year olds scheduled for neurodevelopmental evaluation. ASD case classification as determined by three novel assessment instruments (the Early Video-guided Autism Screener E-VAS; the Autism Symptom Interview, ASI; the Screening Tool for Autism in Toddlers Expanded, STAT-E) each designed to be administered in less than 30 minutes by lay staff, was compared to ADOS scores and DSM-based diagnostic assessment from a qualified clinician. Sensitivity and specificity of each instrument alone and in combination were estimated. Alternative cutpoints were identified under different criteria and two-stage cross validation was used to avoid overfitting. Findings were interpreted in the context of a large, prospective pregnancy cohort study utilizing a two-stage approach to case identification. Under initial cutpoints, sensitivity ranged from 0.63 to 0.92 and specificity from 0.35 to 0.70. Cutpoints giving equal weight to sensitivity and specificity resulted in sensitivity estimates ranging from 0.45 to 0.83 and specificity ranging from 0.49 to 0.86. Several strategies were well-suited for application as a second-stage case-confirmation. These included the STAT-E alone and the parallel administration of both the E-VAS and the ASI. Use of more streamlined methods of case-confirmation in large-scale prospective cohort epidemiologic investigations of ASD risk factors appears feasible. Autism Res 2017, 10: 485-501. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]