Women's reproductive health and its relation to diabetes and cardiovascular health.

Heart disease and diabetes are the leading causes of death and disability worldwide accounting for over a quarter of all deaths in the UK. When and how women experience reproductive events, such as when did their periods start or stop, was their pregnancy complicated and have they used hormones are readily available information and have all been linked with heart disease or diabetes in later life. It is unknown whether combining these information about reproductive events will facilitate better and earlier identification of women at risk of heart disease and diabetes, before they develop overt disease when interventions can be of greatest benefit.
I will:
1. Examine how both single and combinations of multiple reproductive events are linked with future heart disease and/or diabetes.
2. Identify whether reproductive events themselves contribute to future heart disease and/or diabetes and the biological mechanisms involved.
3. Determine whether knowledge of these reproductive events enables better identification of women at high risk.
To achieve these aims I will use several established cohort studies with data from more than 250,000 women. These cohorts have a wealth of complementary data regarding reproductive health indicators, reproductive hormones, lifestyle factors (such as smoking, physical activity or diet) as well as disease outcomes. I will use a variety of analytical methods to distinguish between mere associations and those that reflect a direct effect of reproductive health on the risk of heart disease and diabetes. I will also examine whether my findings are applicable in different datasets or at a population level (by using data on all women giving birth in Scotland from 1969 onwards) to ascertain if knowledge of these reproductive events can predict better independent or in combination with already existing risk factors (such as blood pressure, lipids etc) the risk of a woman developing heart disease or diabetes in the future.

Single indicators of reproductive health in women (e.g. earlier age of menarche or menopause, hormonal use, cycle irregularity, pregnancy complications, parity and menopausal symptoms) are associated with greater risk of diabetes or cardiovascular disease (CVD). However, whether collectively they can improve risk stratification or facilitate better understanding of the aetiology of cardiometabolic diseases in women is unknown.
I aim to:
1. Examine the separate and joint associations of multiple reproductive indicators with cardiometabolic outcomes.
2. Identify causal effects of reproductive indicators on cardiometabolic diseases.
3. Determine whether reproductive indicators can improve risk prediction for diabetes and CVD.
I will address these by using data from established cohorts (Generation Scotland, UK Biobank) or population level datasets, which are complementary in terms of richness of phenotype and sample size. Using multiple analytical approaches and establishing consistency of my findings across these strategies, and replicating the findings across the cohorts will enhance the validity of the findings. Analytical approaches will include multiple regression, structural equation modelling, G-computation and Mendelian randomisation.
The findings of the project will enable early identification of women at risk of diabetes and CVD, thus facilitating timely interventions.

My fellowship application is translational in that the intention is to develop better approaches to predicting risk and targeting preventive strategies, for use in clinical practice. It grew out of early engagement with stakeholders (NICE, Scottish Intercollegiate Guideline Network, Joint British Societies consensus for cardiovascular disease prevention and international guidelines) and will help to address their need to find more effective strategies to improve women's health and reduce gender based health inequalities. General consensus agrees that existing risk scores do not perform well in women underestimating their overall increased lifetime risk of cardiovascular events. The relevant stakeholders have recognised the wealth of data accrued from reproductive events and their potential contribution to predicting long-term cardiometabolic disease but currently lack the information necessary to realise that potential. A better understanding of how to translate a complex series of reproductive events into meaningful prediction could improve existing risk scores, inform national and international guideline committees, update clinical protocols and scientific policy papers and change clinical practice. Thus, implementation of risk models that perform better than existing ones in identifying women at high risk of future disease will enable earlier intervention when the disease progression is more likely to be reversed or delayed. The updated risk scores will be likely to become clinically applicable and provide alternative approaches for use in low resource settings where laboratory access and, thereby, the use of biomarkers is limited.
Having the capacity to provide individualised health scores that can be updated as women go through different reproductive events and target those at high risk with intensive lifestyle modifications or established preventive policies (e.g. shifting a greater proportion of middle aged women towards statins or metformin) will improve public health awareness, modify individuals' risk and have the potential to alter disease burden. In addition, there is evidence suggesting that personalised risk scores rather than generalised public health messages are more likely to impact on individuals' lifestyles and induce healthier choices. Hence, providing women with their personal risk based on their reproductive trajectory will enhance lifestyle modifications that will improve their quality of life and overall health.
Updating risk scores with reproductive information will not only have the potential to reclassify women to higher risk strata enhancing intensive preventive policies but also to lower risk strata decreasing the frequency of follow up investigations. Hence, the findings of this work are likely to improve the effectiveness of public health services with substantial economic benefits by reducing the cost of unnecessary investigations and increasing the efficiency of preventative policies.
I will ensure the impactful dissemination of the key findings of my work by implementing a two-way engagement plan with the key stakeholders from the very early stages of the project. This will ensure maintaining the clinical relevance of the research questions, the use of appropriate methodology and the meaningful interpretation of the results.