Research into human disease has classically been 'bottom-up', focussing on individual genes. However, the emergence of Systems Biology has prompted a more holistic 'top-down' approach to decoding life. Less than a decade since the complete draft of the human genome was published, we are increasingly in a position to model the interacting constituents of a cell and thus understand molecular perturbations. Given biological systems are rarely attributable to individual molecules and linear pathways, we must understand the complex dynamic interplay as cellular components interact, combine, overlap and conflict. The integrative approach afforded by Network Biology provides us with a powerful toolset to understand the vast volumes of omics data. In this thesis, I investigate both infectious disease, specifically HIV infection and heritable disease. HIV, the causative agent of AIDS, represents an extensive perturbation of the host system and results in hijacking of cellular proteins to replicate. I first introduce the HIV-interaction data and then characterise HIV's hijack, revealing the ways Network Biology can greatly enhance our understanding of host-pathogen systems and ultimately the systems itself. I find a significantly greater propensity for HIV to interact with ''key'' host proteins that are highly connected and represent critical cellular functions. Unexpectedly, however, I find there are no associations between HIV interaction and inferred essentiality and genetic disease-association. I hypothesise that these observations could be the result of ancestral selection pressure on retroviruses to minimise interactions with phenotypically crucial proteins. Investigating inherited disease, I apply a similar integrative approach to determine the relationships between inherited disease, evolution and function. I find that 'disease' genes are not a homogenous group, and that their emergence has been ongoing throughout the evolution of life; contradicting previous studies. Finally, I consider the consequence of bias in literature-curated interaction datasets. I develop a novel method to identify and correct for ascertainment bias and demonstrate that failure to do this weakens conclusions. correct for ascertainment bias and demonstrate that failure to do this weakens conclusions. The aim of this thesis has been to explore the ways Network Biology can provide an integrative biological approach to studying infectious and inherited disease. Given billions of people around the world are susceptible to disease, it is ultimately hoped that a Systems Biology approach to understanding disease will herald new pharmaceutical interventions.

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Background: The aim of this cross-sectional study was to investigate oral health and functional status of adolescents with juvenile idiopathic arthritis (JIA) and its possible link to disease specific parameters. Methods: Patients with JIA were recruited (November 2012–October 2014) and disease specific information was extracted from patients’ records. Oral examination included: dental findings (decayed-, missing- and filled-teeth-index (dmf-t/DMF-T)), gingival inflammation (papilla-bleeding-index (PBI)) and periodontal screening index (PSI). Functional examination followed Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Additionally, modified Helkimo’s Clinical Dysfunction Index and radiographic scoring were recorded. Results: 59 JIA patients were included. The mean dmf-t/DMF-T was 2.6. Only one patient showed no signs of gingival inflammation, while 57.6% had a maximum PSI of 2 or less. Positive functional findings were assessed clinically in more than half of the patients. Major diagnosis by RDC/TMD was osteoarthrosis. Patients with at least one positive anamnestic or clinical functional finding revealed significantly higher radiographic scores (CI = 0.440, p = 0.022). Patients with increased c-reactive-protein had a significantly higher PBI (Z = –2.118, p = 0.034) and increased radiographic scores (CI = 0.408, p = 0.043). Conclusions: Adolescents suffering from JIA show high levels of caries experience and gingival inflammation. Temporomandibular joint dysfunction is often seen in JIA patients. Consequently, special dental care programs would be recommendable.

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