Advances in new technologies, when incorporated into routine health screening, have tremendous promise to benefit children. The number of health screening tests, many of which have been developed with machine learning or genomics, has exploded. To assess efficacy of health screening, ideally, randomized trials of screening in youth would be conducted; however, these can take years to conduct and may not be feasible. Thus, innovative methods to evaluate the long-term outcomes of screening are needed to help clinicians and policymakers make informed decisions. These methods include using longitudinal and linked-data systems to evaluate screening in clinical and community settings, school data, simulation modeling approaches, and methods that take advantage of data available in the digital and genomic age. Future research is needed to evaluate how longitudinal and linked-data systems drawing on community and clinical settings can enable robust evaluations of the effects of screening on changes in health status. Additionally, future studies are needed to benchmark participating individuals and communities against similar counterparts and to link big data with natural experiments related to variation in screening policies. These novel approaches have great potential for identifying and addressing differences in access to screening and effectiveness of screening across population groups and communities.