Stability of Ranked Gene Lists in Large Microarray Analysis Studies

This paper presents an empirical study that aims to explain the relationship between the number of samples and stability of different gene selection techniques for microarray datasets. Unlike other similar studies where number of genes in a ranked gene list is variable, this study uses an alternative approach where stability is observed at different number of samples that are used for gene selection. Three different metrics of stability, including a novel metric in bioinformatics, were used to estimate the stability of the ranked gene lists. Results of this study demonstrate that the univariate selection methods produce significantly more stable ranked gene lists than the multivariate selection methods used in this study. More specifically, thousands of samples are needed for these multivariate selection methods to achieve the same level of stability any given univariate selection method can achieve with only hundreds

Ranking causal variants and associated regions in genome-wide association studies by the support vector machine and random forest

We study the number of causal variants and associated regions identified by top SNPs in rankings given by the popular 1 df chi-squared statistic, support vector machine (SVM) and the random forest (RF) on simulated and real data. If we apply the SVM and RF to the top 2r chi-square-ranked SNPs, where r is the number of SNPs with P-values within the Bonferroni correction, we find that both improve the ranks of causal variants and associated regions and achieve higher power on simulated data. These improvements, however, as well as stability of the SVM and RF rankings, progressively decrease as the cutoff increases to 5r and 10r. As applications we compare the ranks of previously replicated SNPs in real data, associated regions in type 1 diabetes, as provided by the Type 1 Diabetes Consortium, and disease risk prediction accuracies as given by top ranked SNPs by the three methods. Software and webserver are available at http://svmsnps.njit.edu

Algorithms in comparative genomics

The field of comparative genomics is abundant with problems of interest to computer scientists. In this thesis, the author presents solutions to three contemporary problems: obtaining better alignments for phylogeny reconstruction, identifying related RNA sequences in genomes, and ranking Single Nucleotide Polymorphisms (SNPs) in genome-wide association studies (GWAS). Sequence alignment is a basic and widely used task in bioinformatics. Its applications include identifying protein structure, RNAs and transcription factor binding sites in genomes, and phylogeny reconstruction. Phylogenetic descriptions depend not only on the employed reconstruction technique, but also on the underlying sequence alignment. The author has studied and established a simple prescription for obtaining a better phylogeny by improving the underlying alignments used in phylogeny reconstruction. This was achieved by improving upon Gotoh\u27s iterative heuristic by iterating with maximum parsimony guide-trees. This approach has shown an improvement in accuracy over standard alignment programs. A novel alignment algorithm named Probalign-RNAgenome that can identify non-coding RNAs in genomic sequences was also developed. Non-coding RNAs play a critical role in the cell such as gene regulation. It is thought that many such RNAs lie undiscovered in the genome. To date, alignment based approaches have shown to be more accurate than thermodynamic methods for identifying such non-coding RNAs. Probalign-RNAgenome employs a probabilistic consistency based approach for aligning a query RNA sequence to its homolog in a genomic sequence. Results show that this approach is more accurate on real data than the widely used BLAST and Smith- Waterman algorithms. Within the realm of comparative genomics are also a large number of recently conducted GWAS. GWAS aim to identify regions in the genome that are associated with a given disease. The support vector machine (SVM) provides a discriminative alternative to the widely used chi-square statistic in GWAS. A novel hybrid strategy that combines the chi-square statistic with the SVM was developed and implemented. Its performance was studied on simulated data and the Wellcome Trust Case Control Consortium (WTCCC) studies. Results presented in this thesis show that the hybrid strategy ranks causal SNPs in simulated data significantly higher than the chi-square test and SVM alone. The results also show that the hybrid strategy ranks previously replicated SNPs and associated regions (where applicable) of type 1 diabetes, rheumatoid arthritis, and Crohn\u27s disease higher than the chi-square, SVM, and SVM Recursive Feature Elimination (SVM-RFE)