Project Summary With the availability of the high-through sequencing technology, the scientific community is now able to investigate complex phenotypes at both organismal and molecular levels. Nevertheless, it is still considerably difficult to perform controlled experiments and randomized trials to investigate the causal relationships between phenotypes at different levels. It is therefore critically important to perform causal inference based on the observational data. In this project, we will develop computational methods to facilitate systematic investigation of causal molecular mechanisms underlying complex disease process. Specifically, we will target three outstanding scientific issues: i) casual inference of molecular mechanisms of complex diseases; ii) analytic approaches for risk prediction utilizing genomic information and causal molecular mechanisms, and iii) statistical assessment of reproducibility in high-throughput genomic experiments. Finally, we will build user-friendly computational software packages and make them available to the broad community of biological and medical scientists.