MOTIVATION: Meta-analysis methods have been widely used to combine results from multiple clinical or genomic studies to increase statistical powers and ensure robust and accurate conclusions. The adaptively weighted Fisher's method (AW-Fisher), initially developed for omics applications but applicable for general meta-analysis, is an effective approach to combine P-values from K independent studies and to provide better biological interpretability by characterizing which studies contribute to the meta-analysis. Currently, AW-Fisher suffers from the lack of fast P-value computation and variability estimate of AW weights. When the number of studies K is large, the 3K - 1 possible differential expression pattern categories generated by AW-Fisher can become intractable. In this paper, we develop an importance sampling scheme with spline interpolation to increase the accuracy and speed of the P-value calculation. We also apply bootstrapping to construct a variability index for the AW-Fisher weight estimator and a co-membership matrix to categorize (cluster) differentially expressed genes based on their meta-patterns for intuitive biological investigations. RESULTS: The superior performance of the proposed methods is shown in simulations as well as two real omics meta-analysis applications to demonstrate its insightful biological findings. AVAILABILITY AND IMPLEMENTATION: An R package AWFisher (calling C++) is available at Bioconductor and GitHub (https://github.com/Caleb-Huo/AWFisher), and all datasets and programing codes for this paper are available in the Supplementary Material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Supervised machine learning is commonly applied in genomic research to construct a classifier from the training data that is generalizable to predict independent testing data. When test datasets are not available, cross-validation is commonly used to estimate the error rate. Many machine learning methods are available, and it is well known that no universally best method exists in general. It has been a common practice to apply many machine learning methods and report the method that produces the smallest cross-validation error rate. Theoretically, such a procedure produces a selection bias. Consequently, many clinical studies with moderate sample sizes (e.g. n = 30-60) risk reporting a falsely small cross-validation error rate that could not be validated later in independent cohorts. RESULTS: In this article, we illustrated the probabilistic framework of the problem and explored the statistical and asymptotic properties. We proposed a new bias correction method based on learning curve fitting by inverse power law (IPL) and compared it with three existing methods: nested cross-validation, weighted mean correction and Tibshirani-Tibshirani procedure. All methods were compared in simulation datasets, five moderate size real datasets and two large breast cancer datasets. The result showed that IPL outperforms the other methods in bias correction with smaller variance, and it has an additional advantage to extrapolate error estimates for larger sample sizes, a practical feature to recommend whether more samples should be recruited to improve the classifier and accuracy. An R package 'MLbias' and all source files are publicly available. AVAILABILITY AND IMPLEMENTATION: tsenglab.biostat.pitt.edu/software.htm. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: With the rapid advances and prevalence of high-throughput genomic technologies, integrating information of multiple relevant genomic studies has brought new challenges. Microarray meta-analysis has become a frequently used tool in biomedical research. Little effort, however, has been made to develop a systematic pipeline and user-friendly software. In this article, we present MetaOmics, a suite of three R packages MetaQC, MetaDE and MetaPath, for quality control, differentially expressed gene identification and enriched pathway detection for microarray meta-analysis. MetaQC provides a quantitative and objective tool to assist study inclusion/exclusion criteria for meta-analysis. MetaDE and MetaPath were developed for candidate marker and pathway detection, which provide choices of marker detection, meta-analysis and pathway analysis methods. The system allows flexible input of experimental data, clinical outcome (case-control, multi-class, continuous or survival) and pathway databases. It allows missing values in experimental data and utilizes multi-core parallel computing for fast implementation. It generates informative summary output and visualization plots, operates on different operation systems and can be expanded to include new algorithms or combine different types of genomic data. This software suite provides a comprehensive tool to conveniently implement and compare various genomic meta-analysis pipelines. AVAILABILITY: http://www.biostat.pitt.edu/bioinfo/software.htm CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.