Research Pillar: Clinical

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.

BRIDGE-MTB: Bringing Integrated Data, Genomics, and Evaluation to Mycobacteria and Tuberculosis

Tuberculosis (TB) and non-tuberculous mycobacterial infections (NTMs) are bacterial infections that create serious problems in BC. Treating TB costs the health system nearly $13 million per year, and NTMs are emerging as a new and poorly-understood threat, especially in BC’s seniors.

My previous work has shown that we can get faster and cheaper information by replacing standard TB/NTM lab tests with a single genome sequence test on the bacteria. It has also shown that comparing the mutations in the genomes of bacteria from different patients allowed us to reconstruct the timeline of an outbreak, deducing who infected whom and when.

BRIDGE-MTB is a five-year province-wide program that will expand my previous work to explore three key areas:

  1. If we use genomics to diagnose and phenotype every single mycobacterial isolate coming into our provincial lab, will it still prove better and faster than traditional laboratory methods? How will it improve our health delivery systems? How will it improve patient outcomes?
  2. By looking for shared mutations in TB and NTM genomes, can we discover where, why and how TB and NTMs are spreading in BC? Can we use this technique of genomic epidemiology to control outbreaks?
  3. The genomic data is complex. Can we design a clinical report that summarizes it in an intuitive, interpretable way for our doctors and nurses?    

BRIDGE-MTB seeks to improve BC's practice and policy on testing, treating, controlling and understanding TB and NTMs.

A computer-assisted method for dental implant procedures using drilling sounds

A dental implant is a screw-like device that is surgically placed in the jawbone to provide a foundation for artificial teeth. This involves precise removal of bone using drills, which is often risky because of proximity to delicate structures such as the maxillary sinus, orofacial nerves, and blood vessels. Mistakes in the drilling path may result in permanent nerve damage, life threatening hemorrhage, or injuries to adjacent teeth. This research project aims to reduce errors in the process by developing an objective and sensor-based method to assist practitioners in conducting the drilling process.

Our method will analyze the sounds generated during implant drillings to monitor the process and recognize different bone tissues, providing real-time feedback on whether the practitioner is taking the correct line. Proof of concept exists in that drilling sounds have already been used in similar applications to discriminate between tooth materials.

To collect the data, we will drill sample jawbones (pig or cow) as we would in typical implant surgeries. We will record the sounds produced by drilling bone tissues under different conditions such as direction, feed rate, speed, and applied forces. Advanced signal processing methods such as machine learning will analyze the data to allow us to discriminate between different bone tissues.

We will optimize the resulting algorithm to produce an aid for practitioners that will improve the safety and precision of their dental implant surgeries. Future work could include further customizing the algorithm to extend its use to other medical procedures that involve bone drilling such as orthopedics, spine, and ear surgeries.

Mutant cell-free DNA as a non-invasive blood test to monitor pancreatic cancer

Close to 5,000 Canadians are diagnosed with pancreatic cancer every year and it is the fourth most common cause of cancer-related deaths in Canada. Unfortunately, a majority of these patients die within a year of their diagnosis, due in part to late diagnosis and tumour resistance to chemotherapy. In addition, most patients who are successfully treated eventually recur and succumb to the disease.

There is a need for reliable blood tests for more routine diagnosis, monitoring treatment response, and detecting tumour recurrence in pancreatic cancer patients. We seek to develop such tests using cell-free DNA in the blood. Mutant forms of cell-free DNA that originate from tumours can be detected in the blood of patients with pancreatic cancer, and this project will explore how we can use it to:

  1. Diagnose pancreatic cancer earlier
  2. Detect cancer recurrence earlier
  3. Identify patients whose tumours do not respond to chemotherapy in order to help guide treatment decisions

We will collect blood from patients who have undergone surgical removal of pancreatic cancers and follow their progress over two years to examine whether we can detect cancer recurrence by monitoring the presence of mutant cell-free DNA after surgery. We will also collect blood from patients with advanced stage pancreatic cancer who are undergoing treatment to explore whether changes in mutant cell-free DNA levels predict whether their tumours respond to chemotherapy.

In these ways, a non-invasive blood test will help to improve quality of life and optimize treatment for thousands of Canadians diagnosed with pancreatic cancer.

A telehealth intervention to promote healthy lifestyles after stroke: The Stroke COACH

Stroke is often associated with low levels of physical activity and poor nutrition habits and with related conditions such as obesity, hypertension and diabetes. Within five years of the initial stroke, 30 percent of stroke survivors will suffer a recurrent stroke.

We developed the telehealth Stroke COACH programme, a lifestyle modification intervention comprised of a self-management manual for stroke survivors, a self-monitoring kit (including a blood pressure monitor, pedometer, and health report card), and telephone-coaching sessions by trained ‘lifestyle coaches’. In this six month program, seven sessions of 30-60 minutes are delivered by the coaches who use motivational interviewing techniques to facilitate active patient engagement and enhance chronic disease self-management skills of problem solving, decision making, action planning, and resource utilization.

One hundred twenty-five community-dwelling individuals who have had a stroke of mild to moderate severity within the last twelve months will be enrolled in this single-blind randomized controlled trial. They will be randomly assigned to either: 1) Stroke COACH with a lifestyle coach, or 2) control group (memory training program with a memory coach).

We predict that the Stroke COACH will improve a global measure of lifestyle behaviour in community-dwelling stroke survivors compared to the control group. This will be measured at zero, six, and 12 months using the Lifestyle Profile II, a global lifestyle behaviour measure that considers physical activity, stress management, nutrition, health advocacy, interpersonal support, and spirituality.

We also predict improvement in physical activity and cardiovascular health outcomes, which we will measure using the StepWatch Activity Monitor and bloodwork results.

If testing is successful, the low-cost and remote delivery of the Stroke COACH would enable a large number of Canadians in both urban and rural regions to improve health behaviours of people living with stroke, potentially reducing the risk of subsequent stroke.

Using aerobic exercise to enhance motor learning and cortical excitability after stroke

The severity of motor impairments due to stroke vary markedly in different people, and with therapy, a degree of recovery is possible. Understanding the underlying neural mechanisms supporting motor recovery from stroke would inform development of more effective therapies.

The overall objective of the proposed work is to determine whether priming exercise (bouts of aerobic exercise) can alter cortical structure and excitability and prepare the brain to enhance motor learning after stroke. Testing hypotheses based on studies of healthy individuals, we will investigate whether for individuals with stroke:

  1. Neurobiological changes occur following priming exercise
  2. Motor learning is enhanced by repeated pairings of priming exercise with skilled motor practice
  3. There is capacity for neuroplastic change in brain white matter (myelin) following repeated pairings of priming exercise with skilled motor practice

This work could aid in predicting how priming exercise may alter the neurobiology of the brain and impact capacity for motor learning in different individuals.

Pairing rehabilitation with priming exercise could prove to be an effective approach to improving outcomes after stroke. This research may serve as a starting point for using structural imaging information to personalize this approach patient-by-patient for optimal outcomes.

Characterizing Arm Recovery in People with Severe Stroke (CARPSS)

In Canada, there are over 50,000 new strokes reported every year. The prevalence and severity of subsequent upper limb disability is increasing and the prospect of complete recovery is poor. Stroke survivors who lack early indicators of a good prognosis, such as movement at the shoulder or wrist, are considered unlikely to regain much arm function through rehabilitation. However, a growing body of evidence suggests that untapped recovery potential may be better assessed from brain scans.

This project will create a data set that sheds light on 'who recovers' and 'who does not recover' by examining how the severely damaged brain changes over the first year post stroke. A series of brain scans and clinical tests of motor recovery will be performed for fifty adults with severe upper limb impairment after their first stroke. Their upper limb use during training and real world settings will also be documented.

This research will support the development of personalized training approaches that maximize functional recovery following stroke.

Alteration of intestinal microbiota composition and function by co-trimoxazole use and the effect of these changes on growth in HIV-infected children

Malnutrition in early life underlies almost half of all child deaths globally and has long-term negative effects on education and productivity. HIV infection further compounds these effects in sub-Saharan Africa. The World Health Organization (WHO) recommends daily use of the antibiotic co-trimoxazole (CTX) to prevent infections in HIV-infected children. In addition to reducing deaths from infections, CTX also improves growth, possibly by changing the population of "good" microbes in the intestines.

But using antibiotics on a daily basis risks emergence of antibiotic resistant microbes, which could cause disease.

This project will test the hypotheses that daily CTX use in HIV-infected children causes the population of the microbes in their intestines to show:

  1. An increase in the number of antibiotic resistance genes
  2. An increase in the number of genes that encode proteins involved in nutrient harvesting (e.g. carbohydrate digestion)
  3. A decrease in genes involved in virulence
  4. That these changes drive the effect of CTX on growth

We will analyze child growth measurements and clinical data and will characterize genetic changes to the microbiota in stool specimens using DNA sequencing methods. Data and samples were collected through ARROW, a randomized trial designed to study the impact of CTX use on a number of health outcomes in HIV-infected children in Zimbabwe.

Our goal is to understand how daily use of CTX impacts child health in a wider context and to inform WHO recommendations on CTX use in HIV-infected children.

How is the motor learning capacity of a skilled walking task affected after an incomplete spinal cord injury?

Many people who have an incomplete spinal cord injury (iSCI) have the potential to improve their ability to walk. Current training strategies are limited in their ability to target skilled walking tasks (e.g. stairs and obstacles).

Sensory function can be affected after iSCI. We believe that this could influence success at re-learning these tasks, because previous studies show that impaired sensory feedback from the leg muscles can influence how the foot moves while walking.

The goal of this work is to investigate how well people with an iSCI can re-learn a new skilled walking task, and to evaluate the impact of impaired sensory function in the lower limbs on this process.

Our findings will shed light on how reduced sensory function affects people re-learning skilled walking tasks after iSCI.

Behavioural and neural correlates of placebo responses in healthy and clinical populations

Michael Smith Foundation for Health Research/Lotte and John Hecht Memorial Foundation Post-Doctoral Fellowship Award

Placebo effects pose challenges to the conduct of clinical research. Double-blind randomized placebo-controlled trials can demonstrate superiority of an active intervention to a placebo. However, in some cases placebo control / complete blinding is difficult or impossible. For instance, in invasive or surgical interventions, placebo use raises ethical questions.

Susceptibility to placebo effects varies substantially across individuals: some experience pronounced placebo effects, while others show little or no response. Sources of this variation are poorly understood. Recent evidence from basic research has pointed to the role of reward expectancy and neural reactivity to rewards as key mechanisms of placebo response.

We seek to identify predictors of individual placebo responses in a sample of healthy volunteers, focusing on reward expectancy and reactivity. We will also examine individual variation in placebo response in an ongoing randomized controlled trial of an endovascular procedure in multiple sclerosis at UBC.

Understanding individual variation in placebo response could ultimately be used in clinical research:

  1. To model placebo-related variance of patients in clinical trials where placebo control is impossible or problematic
  2. To guide selection of patients for clinical trials