Enabling precision management of glaucoma through discovery of underlying biological pathways and clinical prediction tool development

People fear losing their vision as much as developing dementia or cancer. Glaucoma is the leading cause of incurable blindness globally, affecting over 80 million people. In the early stages of glaucoma, there are usually no symptoms and people are unaware they have the disease. By the time vision loss is apparent, there has already been considerable irreversible damage. Therefore, early detection of glaucoma is critical for preventing blindness. In the UK, glaucoma is detected opportunistically at community optometrists when people attend for eye checks. There is no formal screening programme as current screening tests are inadequate. Once diagnosed, treatment is usually for life and glaucoma is a major burden on healthcare services with over 1 million National Health Service (NHS) outpatient visits per year in the UK. We are currently unable to predict which glaucoma patients need most intensive therapy, meaning some patients still develop blindness despite treatment and other patients are likely overtreated. We are also unable to predict which of the many treatment options will be optimal for individual patients and the current standard of care is trial and error. All these challenges, in combination with the rapidly increasing number of glaucoma sufferers due to the ageing population, makes glaucoma a major public health challenge. We urgently need to innovate how we detect and treat glaucoma to prevent blindness and make best use of our limited resources.

Glaucoma is a hereditary condition but is "complex", meaning that it is caused by large number of genetic factors acting together. I recently discovered over 100 of these genetic factors for glaucoma using data combined from 14 studies globally. Put together in a prediction model, these factors helped predict who in a population will develop glaucoma. Many more factors need to be discovered, but this opens up the possibility of targeted population screening to enable earlier diagnosis and prevention of irreversible sight loss.

The aims of my research are to:
1. Discover further new genetic factors to better understand the complex nature of glaucoma and better predict which people in a population are at highest risk of the disease
2. Discover other glaucoma-causing biological processes related to variation in levels of different proteins and metabolites in the blood
3. Discover non-genetic factors that predispose to glaucoma, such as diet, exercise and medication use, and to determine if these factors can alter a person's genetic risk for disease
4. Establish a study of glaucoma patients which collects data on their progress over time and combines this with genetic data
5. Determine whether the identified genetic factors can predict which glaucoma patients are at highest risk of blindness and predict individual response to different treatments

If successful, my proposed research will have considerable potential impact. Being able to identify people at high risk of glaucoma on the basis of a genetic test alone will allow targeted screening of these individuals, enabling earlier diagnosis and prevention of irreparable vision loss. If genetic factors predict the course of the disease, it will be possible to help decide which patients need most intensive treatment to prevent blindness and which patients are at low risk to avoid overtreating them. Similarly, it may become possible to select the most effective treatment for each individual patient using genetic information. Put together, genetic testing may allow us to personalise the care of glaucoma patients and direct our limited resources to the patients that need it most. Innovative approaches such as this are essential to deal with the rapidly increasing numbers of glaucoma patients. Additionally, the work identifying the key biological processes that underlie glaucoma will help the development of new drug treatments.

My research aims to enable personalised glaucoma management, directing care to the highest risk patients to prevent blindness, and sparing the costs and side-effects of treatment in patients who will not benefit. It additionally aims to elucidate the fundamental processes that underlie glaucoma and identify targets for new treatments. This proposal addresses three of the top 10 research priorities for glaucoma as identified by the James Lind Alliance national consultation of patients, carers, relatives and eye health professionals ("what can be done to improve early diagnosis of sight-threatening glaucoma?", "what causes glaucoma?", and "how can glaucoma patients with a higher risk to progress rapidly be detected?").

In addition to providing wide-ranging facilitation of future research across multiple disciplines (see Academic Beneficiaries), my research programme will benefit the following groups:

GLAUCOMA PATIENTS: I will develop risk prediction models that will enable innovative and improved care for glaucoma patients. The risk of blindness due to glaucoma will be reduced by 1) earlier detection of disease from improved population screening, and 2) by earlier intensive treatment of patients at highest risk of vision loss following diagnosis. Conversely, patients at low risk of blindness will also be identified by the risk prediction models. For these patients, there will be reduced anxiety, less side effects and less unnecessarily aggressive treatment or frequent hospital visits. Additionally, new treatments developed from targets identified from the proposed research have potential to reduce blindness in the longer-term. Patients will also be empowered to help control their disease with lifestyle modifications which were identified by the proposed research.

CARERS OF GLAUCOMA PATIENTS: Reduced blindness in high-risk patients and reduced need for treatment or hospital visits in low-risk patients will both mean less burden on the carers of glaucoma patients.

GENERAL PUBLIC: The public are screened for glaucoma at their local optometrist. This frequently prompts unnecessary referral to the hospital eye services for further assessment, due to the poor predictive ability of current screening tests. Targeted screening of people at high genetic risk of glaucoma will improve the predictive ability of current tests and reduce the unnecessary referrals and the associated costs and anxiety.

GOVERNMENT AND TAXPAYERS: Glaucoma healthcare costs will be lowered by reducing treatment and follow-up for glaucoma patients that do not require it, enabling a strategy for managing the rapidly increasing numbers of people with glaucoma.

HEALTHCARE PROVIDERS: Limited resources will be directed to patients that need it the most and less time and resources will be wasted on patients who do not require it. This provides the 'gift of time' for healthcare practitioners managing more complex patients, and reduces stress for healthcare providers who are currently very stretched (over 1 million glaucoma-related visits in the NHS per year).

OPHTHALMIC AND RELATED INDUSTRIES: Productivity and revenue will increase for electronic medical record (EMR) providers (by incorporating clinical prediction tools), genotyping companies (by increasing testing as part of clinical care) and pharmaceutical companies (by improved outcomes for existing drugs due to enabled personalised care, and development of new treatments from targets identified). I am actively working with Medisoft and OpenEyes EMR providers and am a consultant to several pharmaceutical companies. Specifically, I am advising Aerie and Allergan on incorporation of genetic testing into their clinical trials, to identify predictors of response, enabling targeted and value-based prescribing.