Managed Alcohol Programs: Evaluating Effectiveness and Policy Implications

This research project builds on Dr. Pauly’s 2013 CIHR-PHSI award supported by MSFHR to evaluate the outcomes and implementation of Managed Alcohol Programs (MAPS). The objectives of MAPs are to reduce harm by facilitating greater stability in housing, reducing consumption of hazardous non-beverage and reducing social problems associated with heavy drinking episodes.

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Advancing Healthcare Diagnostics for Neurodegenerative Disorders

Alzheimer’s disease causes progressive neurological decline and substantially decreases the quality of life of patients and their caregivers. In 2011, 747,000 Canadians had Alzheimer’s disease or another form of dementia. With a rapidly aging population, this figure is projected to rise to 1.4 million by 2040, costing $293 billion/year, thus representing an urgent and rapidly growing healthcare issue.

Early and accurate diagnosis of Alzheimer’s disease is critical because timely access to healthcare and community services has the potential to slow disease progression and improve quality of life. Current approaches for diagnosis rely on traditional imaging tests and observation of the signs and symptoms of the disease. Adding the measure of proteins found in cerebrospinal fluid (biomarkers) helps doctors correctly identify the disease. This project aims to create better tools for timely diagnosis of Alzheimer’s disease and other dementias, and make these tools easily accessible to those that need them.

This program of research will develop a comprehensive understanding of how biomarkers for Alzheimer’s disease impact clinical decision making and healthcare costs. It will develop an Alzheimer’s disease diagnostic tool and with input from patients, their families, their doctors and other relevant stakeholders, address barriers to uptake and use in the healthcare system. In addition to Alzheimer’s disease, this research will investigate development of diagnostic technologies for related disorders such as frontotemporal dementia and Lewy body dementia.

The ultimate goals of this work are to build a diagnostic platform for early detection and diagnosis of cognitive impairment; establish BC as a leader in neurodegenerative diagnostics; and ease the psychological, physical and financial burdens for people with dementias and their families.

Chemical suppression of nonsense mutations for the treatment of Frontotemporal Dementia

Michael Smith Foundation for Health Research/Pacific Alzheimer Research Foundation Scholar Award

Frontotemporal dementia is a progressive neurodegenerative syndrome, and the second most common cause of young-onset dementia after Alzheimer’s disease. Members of our team recently reported that loss-of-function mutations in the gene for a protein called progranulin cause 25 percent of frontotemporal dementia cases. Of these mutations, 30-40 percent are “nonsense mutations” that act as stop signs to prematurely end a process required to produce normal progranulin. When progranulin production ends too early, it leads to a shortened protein that cannot carry out the normal brain functions, eventually leading to dementia in the sixth decade.

The goal of this project is to investigate small molecule combinations that can bypass the abnormal "stop sign” in the progranulin gene, increasing the normal production of this important protein. The small molecule combinations will be refined and optimized to find the most effective combination. This approach, also referred to as “suppression of nonsense mutations”, offers the possibility of developing a new drug for patients with frontotemporal dementia cause by a progranulin mutation. The team also plans to develop a mouse model of frontotemporal dementia to test the small molecule combinations in a living organism.

The long-term goal of the project is to bring new drugs for frontotemporal dementia into clinical trials. An effective therapy would alleviate the devastating impact of dementia in many patients and their families, in BC and beyond. 

CALOR: Cooling Autoinflammation with cLinically Oriented Research

MSFHR/Cassie and Friends Society for Children with Juvenile Arthritis and Other Rheumatic Diseases Scholar Award

Childhood rheumatic diseases such as juvenile arthritis, lupus, vasculitis and fever syndromes are the most common childhood chronic illnesses. In Canada, the diseases affect approximately 10,000 children and youth. The affected children have recurrent attacks of inflammation in joints, muscles, and critical organs due to inappropriate activation of blood cells and molecules in the immune system.  Some rheumatic diseases are life- or organ-threatening and all have significant potential for lifelong poor health and disability. There are no cures and few treatments that are specific and safe for a growing child.

This project, CALOR (Cooling Auto-inflammation with CLinically Oriented Research), aims to develop ways to better measure inflammation in these diseases, especially low levels of inflammation that, if present, may justify continuation or re-starting of therapy to stave off an inflammatory attack. The project uses advanced informatics and a systems biology approach, including novel cellular phenotyping of first responder cells of the innate immune system, to find markers of inflammation.

Project outcomes may include sensitive measures of subclinical inflammation that better direct treatment decisions for children with a rheumatic disease. Central to the approach is early engagement of clinicians and patients to establish research priorities, to connect affected families with each other, and ultimately to identify ways to support BC family doctors so that ongoing patient care can be close to home. The CALOR project is founded on a recently developed Canadian Auto-inflammation Disease Registry and a nucleus of invested clinicians, researchers and families at BC’s Children’s Hospital.

Transforming Urban Form for Mobility: Interventions to improve population health

Governments are making major investments in transit, cycling, and walking infrastructure to alleviate the pressures of traffic congestion and emissions. These changes may have lasting impacts on population health.

The aim of this five-year program is to generate new evidence on the impact of population health interventions on health and health equity along two lines: 
 

  1. "Population Health Intervention Research" will generate new knowledge on the impact of population-level interventions on mobility.
  2. "Methods and Tools for Intersectoral Action" will develop and apply novel methods and tools to study urban form, and to facilitate uptake by intersectoral stakeholders.

This work aims to generate new, locally-relevant evidence in order to understand how to enhance health and mobility in mid-size cities and suburbs. While these settings are very common in Canada, they are surprisingly absent from the literature.

The program will assess how changes to urban form, such as new cycling networks or education programs, influence how people choose to travel, and how safety-conscious and active they are. This will be studied in the population overall, and also specifically with groups facing greater mobility challenges (e.g. women, new immigrants, older adults). The work will focus on how an investment in a city-wide cycling network for people of all ages and abilities impacts uptake, safety and equity.

Understanding and exploiting genome instability in cancer

Cancer is caused by specific DNA mutations that can arise spontaneously over time. Conditions that increase DNA damage or inhibit DNA repair can promote cancer. Genetic factors that affect a cells’ ability to protect and repair DNA promote cancer formation by causing so-called genome instability, defined as an increase in the frequency with which mutations are passed to daughter cells. Genome instability is a double-edged sword: it can contribute to cancer formation, but it can also help with treatment by sensitizing cancer cells to anti-cancer chemotherapy or radiation treatments.

This program studies how defective RNA molecules may lead to genome instability by binding to DNA. If these hybrid DNA:RNA structures accumulate they can lead to DNA damage, increasing the chance of mutations in the DNA. Focus areas include cancer-associated mutations that lead to an increase in DNA:RNA hybrids, determining how and where those hybrids form, and how they might form the basis of new anti-cancer drugs.

The program also investigates how proteins respond to DNA damage. When a protein is made, it must fold into a three-dimensional structure and assemble with other biological molecules to perform its function. In response to DNA-damaging stress, cells can promote survival by halting this process and sequestering newly-made or damaged proteins in a regulated way. Characterizing the network of protein changes that occurs after DNA damage could help with understanding how cells cope with ongoing genome instability or treatment with chemotherapies that damage DNA.

Respiratory Evaluation Sciences Program: Innovations in analytic approaches to improve efficiency in respiratory care

Asthma and chronic obstructive pulmonary disease (COPD) are among the most prevalent chronic diseases in Canada. This research program aims to improve patient outcomes and the efficiency of health care delivery in chronic respiratory diseases like asthma and COPD. The outputs of this research program will help enable evidence-informed decision making at all levels of care.

I analyze existing health data to gain insight into disease burden and gaps in care. I also perform economic evaluations that translate such knowledge into policy-relevant messages on cost-effectiveness of interventions, programs, and policies. Together, these components complete a logical pathway from answering "how big the problem is", to "what the available options are to tackle the problem", and to "what intervention provides the best health value for the resources it consumes".

The project that showcases this program of research is the Evaluation Platform in COPD (EPIC). Through this project, I am leading a pan-Canadian team of experts to develop a computer model of COPD that can be used to predict the outcomes of interventions and policies. EPIC will be capable of modeling the health and cost consequences of many different interventions along the entire pathway of care for COPD (e.g. smoking cessation programs, treatments for COPD, providing better community care, etc.).

Knowledge translation activities through this program will be aimed at raising awareness and usage of analytical decision making in resource allocation. This will be approached through a policy-practice-research partnership, an ongoing interaction between policy makers, best practice experts, and my research team. An established patient advisory committee is ensuring my research remains patient-oriented.

By improving our ability to make evidence-informed decisions at multiple levels of care, this program aims to provide a lasting benefit to the health of Canadians with lung disease and the efficiency of our healthcare system.

Personalized genomics for improving drug safety: From discovery to implementation.

Medications ideally improve patient health, occasionally with mild or moderate side effects. But sometimes patients have significant damaging responses to drugs, events called adverse drug reactions (ADRs). In Canada, there are 87,000 – 200,000 debilitating or life-threatening ADRs, which cause 3,600 – 10,000 deaths each year. The problem is worse in children, where ADRs are three times more life threatening than in adults.

The treatment of childhood cancer is especially impacted by ADRs: a staggering 73 percent of childhood cancer patients develop chronic health conditions from their treatment and 42 percent experience a disability or threat to life.

By better understanding debilitating and life-threatening ADRs in childhood cancer treatment, and generating ADR-predictive tools and prevention strategies, this project aims to benefit the lives of thousands of children and families. Over the past 10 years, collaborations with clinicians, policy makers, and industry partners have generated a sample pool of well-characterized patients for a group of priority ADRs.

This research program will analyze patient DNA to identify genetic factors that help predict ADRs. These will be validated through functional and mechanistic studies. Rapid and cost-effective lab tests will be developed to identify patients at high risk of severe ADRs. Moving knowledge into practice, clinical guidelines will be developed and drug label changes will be pursued, where appropriate, based on the findings.

Ultimately, this work will enable new strategies to protect patients from ADRs. For example, it should be possible to re-purpose certain drugs or use alternative treatment regimes in cases where predictive tools detect a risk of certain ADRs.

The development of novel blood protein biomarkers to enable precision care in cystic fibrosis

Cystic fibrosis is the most common fatal genetic disease, affecting one out of every 3,600 children born in Canada. In 2013 alone, Canadians with cystic fibrosis spent about 25,000 days in hospital, mainly due to pulmonary exacerbations, which cause respiratory distress due to excessive mucus production, infection, and inflammation in the lungs. They are generally managed with two- to three-week courses of intravenous antibiotics and intensive chest physiotherapy. This is gruelling for patients and is costly for the health care system, at nearly $20,000 per episode.

A variety of therapies can prevent or treat pulmonary exacerbations, but to be effective, they need to be given at the right time. This research program aims to develop knowledge and tools that can improve the timing of prescribing and adjusting these therapies to make them more effective.

This program will examine hundreds of blood proteins concurrently, using well-characterized blood samples from cystic fibrosis patients. The proteins will be evaluated for their utility as biomarkers that can be used to predict pulmonary exacerbations and failure of a given course of treatment. Finding biomarkers like this will allow the development of simple blood tests to predict such events. Doctors could use these tests to personalize their courses of treatment to individual patients, thus reducing medical costs and improving patient outcomes.

The ultimate goal of this program is to enable more cost-effective, adaptive, personalized medical care for cystic fibrosis patients through mobilizing biomarker discovery research.

Habitual Physical Activity as Stress Resiliency in Populations Experiencing High Adversity

In light of extensive research linking stress and disease, and the high rates of reported stress in Canadians, there is a need to identify what people can do to protect their health from the ill effects of stress.

My work to date demonstrates that highly stressed and active individuals have significantly healthier biological and psychological stress responses than those who are highly stressed and inactive. This model suggests that physical activity could be helping to protect active individuals against the disease-promoting influences of stress.

This program seeks to clarify whether this is a cause-and-effect relationship. Is the better health of active individuals merely a result of traits that also cause them to remain active when under stress? Or can highly stressed, inactive people also gain these health advantages through interventions that increase their physical activity levels?

Goals of this program include:

  1. Discovering whether increasing habitual physical activity levels in highly stressed and inactive adults reduces the impact of stress on pathways to physical disease.
  2. Developing novel targets for evidence-based intervention programs tailored to individuals with high levels of life stress

Collaboration with researchers, stakeholders in high-risk populations, and policy makers will support the design of interventions that target biological and psychological stress-reactive pathways years before disease appears.

By focusing on health promotion in high-adversity communities, the ultimate goal is to improve quality of life and to reduce the economic burden on our health care system.