Research Questions:
Do key clinical, lifestyle, and genetic factors have a true !causal relationship! with functional outcomes after ischemic stroke (IS)?
Aims:
Aim 1: To quantify the causal effects of genetically proxied clinical traits (e.g., blood pressure, lipids) and lifestyle factors (e.g., physical activity) on post-stroke outcomes (e.g., 3-month mRS score) using a Mendelian Randomization (MR) framework.
Aim 2: To investigate the interactions between polygenic risk scores (PRS) and modifiable risk factors (e.g., exercise) and their combined effects on prognostic outcomes.
Aim 3: To integrate causal risk factors into a clinico-genetic risk prediction model for stroke prognosis, followed by internal validation.
Objectives:
To identify and validate at least 2-3 modifiable factors (e.g., Lp(a) levels, moderate-to-vigorous physical activity) with significant causal effects on stroke prognosis.
To develop an open-source risk scoring tool to aid clinicians in the early identification of patients at high risk of disability.
To provide prioritised causal evidence for designing future targeted interventional trials for stroke rehabilitation.
Scientific Rationale:
Ischemic stroke constitutes 87% of global stroke burden. Despite 40% of ischemic stroke survivors developing functional disability (mRS!3), observational studies suffer from residual confounding. MR overcomes this by leveraging genetic variants as instrumental variables. The current research still lacks a causal assessment of dynamic lifestyle factors (such as the activity intensity monitored by accelerometers) and ischemic stroke. UK Biobank’s trio of genomic data, accelerometry-based activity metrics, and linked hospital records provides unprecedented resources to investigate causal pathways in stroke prognosis.
