PROJECT SUMMARY/ABSTRACT Early, high-risk drinking and drug use during adolescence conveys risk of both acute harms and long-term consequences. NIDA has invested considerable resources in targeted prevention programs to reduce, delay, or mitigate these outcomes. The public health impact of these programs is limited by the current lack of a method to accurately and reliably identify which youth would benefit from these programs before they initiate substance involvement. Existing screening instruments to quantify risk among substance-naïve youth were developed in small, non-representative samples and have not yielded accurate and reliable predictions in new data. Responding to RFA-DA-24-037, Accelerating the Pace of Drug Abuse Research Using Existing Data, we propose to leverage the unprecedented Adolescent Brain and Cognitive DevelopmentSM (ABCD) Study to develop and conduct a preliminary validation of practical, accurate, and equitable screening tools for use in real- world prevention settings. The ABCD Study® is large (N=11,880), sociodemographically diverse, spans 21 cities across the U.S., measured every well-established risk/resilience factors for adolescent substance use, and will be followed prospectively for 10 years, enabling us to distinguish adolescents with early, high-risk drinking/drug use patterns from peers exhibiting developmentally normative, infrequent, and transient experimentation with substances. Thus, no prior study has offered a better opportunity for developing accurate and generalizable screening measures to quantify risk among substance-naïve youth. Aim 1: Develop a portfolio of brief, accurate, equitable, and generalizable screening measures. Following a systematic algorithm designed to maximize accuracy and eliminate inequities, we will construct and refine brief, survey-based measures quantifying risk for early, high-risk drinking and drug use. Aim 2: Conduct a preliminary validation of the developed screening measures in holdout data (n=5,000) weighted to be sociodemographically representative of all children in the U.S Census. To anticipate the tools’ likely performance in real-world settings, we will obtain unbiased estimates of screener performance in holdout data, then conduct sensitivity analyses probing potential limits on generalizability. Together, these aims have potential to deliver screening tools that can unlock the public health potential of existing targeted preventive interventions to reduce early, high-risk drinking/drug use, enabling wider implementation at cost-effective scale. This developmental/exploratory research (R21) leverages existing data to develop novel measures and conduct a preliminary validation. If we are successful at producing measures that yield accurate and equitable screening decisions in holdout data, we will further refine and externally validate the measure in a subsequent R01-scope project.