Integrating economic assessment, multiomics biomarkers and in-silico drug discovery for delirium: a health economics and precision medicine approach

Integrating economic assessment, multiomics biomarkers and in-silico drug discovery for delirium: a health economics and precision medicine approach

Delirium is an acute neuropsychiatric disorder affecting attention, cognition, and consciousness, with incidence rates ranging from 3.3% to 80% in surgical and Intensive Care Unit patients. It results from a complex interplay of aging, cognitive decline, inflammation, neurotransmitter imbalances, oxidative stress, and genetic factors. Delirium imposes significant economic costs, including prolonged hospital stays and long-term care, with Australia’s burden estimated at AU$8.8 billion in 2016-2017. As no effective drug treatment exists, managing delirium requires a multidisciplinary approach with cost-effective healthcare interventions and supports incorporating early screening, prevention, and multidisciplinary care strategies. This thesis explores the economic and precision medicine aspects of delirium through five studies, resulting in seven articles. The "Economic Aspects of Delirium" theme includes systematic reviews, meta-analyses, and cost-effectiveness analysis (CEA) on post-operative delirium (POD) costs, hospital length of stays, and economic evaluations of pharmacological and non-pharmacological interventions. The CEA from an Australian healthcare and social perspective was conducted to assess the effectiveness of a non-pharmacological intervention for delirium prevention and management. The "Precision Medicine for Delirium" theme identifies drug target proteomic biomarkers, their functions, and potential treatments. The studies compile a comprehensive dataset, investigate key biomarkers, and explore molecular links between delirium and Alzheimer’s disease (AD) using bioinformatics and system biology analytical approaches incorporating different statistical tests and methods. The economic assessment shows that POD increases hospital costs and length of stay. The CEA finds the MMHU non-pharmacological intervention to be dominant (less costly, more effective) over standard care under the various willingness-to-pay thresholds. Molecular investigations illustrate key biomarkers and their functions, highlighting the conjugate pathophysiological link between delirium and AD. Molecular dynamic simulations identify ALB and GAD2 as key drug targets, with tacrine and donepezil as top therapeutic candidates for delirium. A meta-analysis confirms the association of cytokines and inflammatory proteins with POD. The outcome of this thesis significantly enriches the existing knowledge about delirium. The cost-effective MMHU intervention warrants further investigation and validation through clinical trials. Rigorous molecular research is needed to establish and validate exclusive drug target biomarkers and computational drugs for their clinical and economic effectiveness. This study lays the inevitable foundation for advancing early detection, personalized therapies, and novel interventions for delirium management.

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