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Shotgun metagenomic sequencing is rapidly becoming the most commonly used approach to identify and quantify complex microbial samples, especially for the study of human gut microbiota. A variety of bioinformatics methods have been developed for shotgun metagenomics data, yet there is still a lot of unresolved issues that limit this technology’s full potential. In this thesis, I examine several important issues that arise from the analysis of shotgun metagenomics data and their application to clinical studies. These issues include: 1. Identifying factors associated with metagenomic species abundance estimation: through benchmarking several key metagenomic sequencing steps such as sample storage, sequencing platform and abundance estimation methods, I identified experimental and bioinformatic factors that influenced the estimation of species abundance estimation. I further proposed a new “gradient framework” to perform quality assessment of individual species abundance estimations. 2. Application of shotgun metagenomic to uncover the association between human gut microbiome and hypertension. Using a cohort of 241 Hong Kong adults, we used various statistical methods with careful covariate adjustment to identify a strong association of gut microbiome and hypertension in females. Specifically, the species Ruminococcus gnavus, Clostridium bolteae, and Bacteroides ovatus were found enriched in hypertensive females. Circulating blood short-chain fatty acid, propionic acid, also associated with gut microbiome and hypertension in females which supports a possible mediating role. 3. Discovery of a novel phenomenon of uneven …