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  • (2022) Kaur, Sandeep
    Advances in molecular biology data collection, leading to the accumulation of large amounts of diverse data, call for novel computational approaches to enable their effective analysis. This thesis explored the application of visual-analytics-driven bioinformatics approaches to four biomolecular data-driven challenges. For analysing time-series omic and multiomic data, a novel method, Minardo-Model, was developed. Minardo-Model can identify key events (e.g. phosphorylation) from such time-series data and temporally order them. To visualise the inferred order of events, two novel visualisation approaches, event maps and event sparklines, were developed. Minardo-Model was tested using two time-series datasets and in both cases, the event orderings derived by this method correlated with prior knowledge. To streamline the use of experimental 3D protein structures for analysing sequence variants, a novel method was developed and integrated into Aquaria. For variants specified in the HGVS notation, the method identifies and displays a best matching structure. Additionally, for each variant specified, all structures spanning the variant, and containing the exact variant (missense only), along with sequence features retrieved from external resources, are summarised. The developed approach was used to analyse variants in human ACE2, and SARS-CoV-2 spike, revealing novel insights. For pathogenic bacterial isolates characterised using multilevel genome typing (MGT), the MGTdb web service was developed. MGTdb, enables upload of isolates as sequence reads or extracted alleles, which are processed and assigned the MGT-identifiers. The features of MGTdb, such as interactive visualisation tools, data download and export to external software, enable epidemiological exploration in the context of the local or global database of isolates. The usability of MGTdb was successfully demonstrated through three case studies. For identifying insertion sequences (IS) from short-read sequencing data, a novel method, WiIS, was developed. WiIS was tested on Bordetella pertussis isolates, for which both short-read (test data) and long-read sequences (ground truth) were available - WiIS was found to have high precision and recall. It also outperformed other published tools in identifying IS in B. pertussis genomes. The novel bioinformatics methods developed in this thesis enable novel analysis of a wide variety of data thus providing insight into various biomolecular processes.

  • (2023) Zillur Rahman, Kazi Mohammad
    Current healthcare infection surveillance rarely monitors the distribution of antimicrobial resistance (AMR) in bacteria beyond clinical settings in Australia and overseas. This results in a significant gap in our ability to fully understand and manage the spread of AMR in the general community. This thesis explores whether wastewater-based monitoring could reveal geospatial-temporal and demographic trends of antibiotic-resistant bacteria in the urban area of Greater Sydney, Australia. Untreated wastewater from 25 wastewater treatment plants sampled between 2017 and 2019 consistently contained extended-spectrum β-lactamases-producing Enterobacteriaceae (ESBL-E) isolates, suggesting its endemicity in the community. Carbapenem-resistant Enterobacteriaceae (CRE), vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) isolates were occasionally detected. Demographic and healthcare infection-related factors correlated with the ESBL-E load, and demographic variables influenced the VRE load. In contrast, the healthcare infection-related factor mainly drove the CRE load. These findings demonstrate the potential of wastewater-based surveillance to understand the factors driving AMR distribution in the community. The subsequent thesis work covers the genomic characterisation of selected ESBL-E and CRE wastewater isolates to reveal their nature, origin, and underlying resistance mechanisms. Phylogenetic analysis showed that Escherichia coli isolates were related to high-risk human-associated pandemic clones and non-human-associated clones. The Klebsiella pneumoniae and K. variicola isolates were related to globally disseminated and emerging human-associated clones, and some were detected for the first time in Australia. Genomic analysis also indicated novel resistance mechanisms against nitrofurantoin in E. coli, and against piperacillin/tazobactam and ticarcillin/clavulanic acid in Klebsiella isolates. The virulence gene content indicated that some E. coli and Klebsiella isolates were likely associated with infections, while the asymptomatic carriage was suggested for other isolates. These results demonstrate a clear potential for wastewater-based surveillance to monitor the emergence and dissemination of resistance in non-clinical isolates, and in particular, isolates from the community and non-human sources. The findings of this study can complement healthcare infection surveillance to inform management strategies to mitigate the emergence and dissemination of AMR and important human pathogens in the general community.