White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

One of the primary concerns in developing computer embedded safety-critical systems is how to develop quality software. Software must fulll its functional requirements and must not contribute to the violation of safety properties of the entire system. To this end, capturing error free and satisfactory functional requirements is crucial before proceeding to the subsequent development phases. We describe an approach to specifying and verifying software for safety-critical systems with the practical formal method SOFL (Structured-Objectbased-Formal Language). Requirements specication focuses on the functionality of the software, but with the consideration of safety constraints and its interaction with the surrounding operational environment. The verication of specications can be carried out using three techniques: data ow reachability checking, specication testing, a n d rigorous proofs, respectively. W e apply this approach to a realistic railway crossing controller for a case study and analyzes its result.