The etiology of schizophrenia (SCZ) is regarded as one of the most fundamental puzzles in current medical research, and its diagnosis is limited by the lack of objective molecular criteria. Although plenty of studies were conducted, SCZ gene signatures identified by these independent studies are found highly inconsistent. As one of the most important factors contributing to this inconsistency, the feature selection methods used currently do not fully consider the reproducibility among the signatures discovered from different datasets. Therefore, it is crucial to develop new bioinformatics tools of novel strategy for ensuring a stable discovery of gene signature for SCZ. In this study, a novel feature selection strategy (1) integrating repeated random sampling with consensus scoring and (2) evaluating the consistency of gene rank among different datasets was constructed. By systematically assessing the identified SCZ signature comprising 135 differentially expressed genes, this newly constructed strategy demonstrated significantly enhanced stability and better differentiating ability compared with the feature selection methods popular in current SCZ research. Based on a first-ever assessment on methods' reproducibility cross-validated by independent datasets from three representative studies, the new strategy stood out among the popular methods by showing superior stability and differentiating ability. Finally, 2 novel and 17 previously reported transcription factors were identified and showed great potential in revealing the etiology of SCZ. In sum, the SCZ signature identified in this study would provide valuable clues for discovering diagnostic molecules and potential targets for SCZ.

Consistent gene signature of schizophrenia identified by a novel feature selection strategy from comprehensive sets of transcriptomic data