Outcome-based Performance Metrics in Canadian Health Care: Moving from “How Many” to “How Well”

Performance in the health sector has conventionally been viewed in terms of volumes, such as the number of additional surgeries that were performed in a given year. Unfortunately, health status and outcomes are not routinely assessed in Canada. This is a substantive concern — imagine the case where your car manufacturer's performance metric did not include car safety and performance but merely focused on production volume. Health status is a more appropriate outcome than volume for assessing system performance, and understanding variation in performance of the health system provides the opportunity to improve patients’ health-related quality of life. This study aims to develop a system to assess the performance of the health care system by measuring what it produces in terms of "health," such as health-related quality of life rather than only measuring the "production of health care" — for example, surgical volumes.

Dr. Jennifer Davis' research will address the use and analysis of “performance metrics” within health care, with a particular focus on patient-centred and outcome-based measures using Patient Reported Outcome Measures (PROMs). PROMs are detailed surveys that allow patients to report important changes as a result of a medical intervention and allow the assessment of health-related quality of life. Thus, instead of just measuring that a surgery took place, PROMs measure the patient’s perception of how the surgery has improved their life.

Dr. Davis will be applying knowledge from fields outside the health care sector, such as engineering and education, to improve performance assessment within the health care sector. By determining how specific measures improve performance outcomes in other fields, and by identifying which of these are most effective, she will then specifically determine the potential to adapt these measures as PROMS within the health care context to enhance the health of Canadians. This critical platform will enable the first performance assessments using a patient-centred and outcome-based approach in Canada.

Elucidating the functions of MCL-1 in DNA repair

Mammalian cells have developed elaborate DNA damage response (DDR) and DNA repair systems in order when to protect and repair their DNA encountering toxic agents. In tumour cells, activation of these molecular events can make tumour cells resistant to chemotherapy or radiotherapy-induced DNA damage. Therefore, decoding how the DDR and DNA repair mechanisms are controlled is very important for understanding how cells become resistant to chemotherapy and to find ways to improve conventional cancer therapies. MCL-1 is a pro-survival protein that has multiple roles within the cell and has been shown to protect cells from death. It can interact with multiple important nuclear proteins involved in DDR response. Loss of MCL-1 increases genome instability after DNA damage. These studies indicate that MCL-1 may be an important component of the DDR machinery to regulate the repair of DNA lesions. Dr. Yemin Wang is investigating how MCL-1 regulates DDR and DNA repair. He is taking an intracellular approach to understand how MCL-1 is delivered into the nucleus after DNA damage and will also use this approach to investigate how MCL-1 regulates crucial events in DDR and DNA repair machinery. Dr. Wang will also examine whether the presence of MCL-1 in the nucleus affects how the cell responds to chemotherapy and whether the role of MCL-1 in DDR affects tumor development. The results of Dr. Wang’s work will provide us with a better understanding of MCL-1 in DDR and DNA repair processes, explain its essential function in vertebrate development, and help us to design improved therapeutic interventions for cancer treatment.

Role of cerebral blood flow in the pathophysiology of central and obstructive sleep apnea

Sleep apnea occurs when a person repeatedly stops breathing for a short period of time while they sleep. This common disorder affects about 20 per cent of Canadians. During sleep apnea episodes, blood oxygen levels fall, resulting in persistent low levels of oxygen, called hypoxia. Consequently, people with sleep apnea commonly experience adverse health outcomes, including high blood pressure, heart attacks and strokes. Preliminary findings from Dr. Philip Ainslie’s research lab have shown that reductions in brain blood flow can worsen sleep apnea, while increases in brain blood flow may reduce it. Dr. Shawnda Morrison’s research will expand on these exciting initial findings by exploring the possibility of treating sleep apnea by manipulating brain blood flow. Dr. Morrison will use sophisticated imaging techniques to examine the effect of an oral medication, which alters brain blood flow, in patients at rest and while they sleep. Her first study will examine patients with and without sleep apnea in a controlled laboratory setting. In her second study, Dr. Morrison will induce sleep apnea in otherwise healthy humans at high altitude (5,000 metres, near the base camp of Mt. Everest, Nepal). In this study, she will also conduct the same experiments on a group of high-altitude residents who do not develop sleep apnea, and compare any differences observed between the two groups. The results of these studies will have major implications for understanding what influences brain blood flow and how these different factors can then affect sleep apnea. Those people who do not develop sleep apnea will provide insight into future sleep apnea treatments. Indeed, these studies will provide a “proof of concept” that an oral medication, which alters brain blood flow, can be an effective treatment for sleep apnea. This will, in turn, dramatically reduce the incidence of heart disease and stroke in patients who have sleep apnea.

The role of emotion regulation in borderline personality disorder and self-injury

Borderline personality disorder (BPD) is among the most complex, misunderstood, and stigmatized mental health problems. It is a serious psychiatric condition characterized by instability in relationships, emotions, identity, and behaviour that often induces intense emotional suffering and places affected individuals at high risk of suicide and self-injury. Approximately 10% of individuals affected by BPD die by suicide, 75% have attempted suicide, and 70-80% self-injure. BPD is also a significant concern for the public health-care system. Patients affected by BPD represent up to 20% of psychiatric inpatients and heavily utilize outpatient and hospital emergency services. In fact, the estimated costs to the health-care system per year for each BPD patient range from US$12,000–$30,000. Self-injury and other problems in BPD appear to be related to problems in the management of emotions, or emotion regulation problems.

Dr. Alexander Chapman’s research aims to better understand and treat BPD and related problems, such as self-injury and suicidal behaviour, by examining the role of emotions in BPD and self-injury. Research in his lab, the Personality and Emotion Research Laboratory, includes a variety of studies aimed at better understanding what causes and maintains BPD and self-injury, as well as studies designed to help us understand how to effectively treat BPD. He is also conducting studies on the risks and protective factors for self-injury.

Dr. Chapman’s short-term goal is to continue to develop his research on BPD in two key areas: (1) the role of emotion regulation in BPD and self-injury, and (2) effective treatments for BPD and NSSI. He has several grants for studies in these areas and hopes to expand this research over the next five years. In the long-term, Dr. Chapman would like to develop an interdisciplinary research, treatment, and education centre focused on BPD, self-injury, and related health problems. Such a centre would be unique in Canada and would have the potential to significantly improve our understanding and treatment of BPD as well as the education and training of junior researchers and professionals.

Treatment of drug-resistant influenza: Rationally designed inhibitors of viral neuraminidase

Each year the influenza virus infects approximately 10% of the human population, resulting in hundreds of thousands of deaths. Even in North America, nearly 40,000 annual “excess deaths” are attributed to influenza or to secondary bacterial infections. Despite a World Health Organization-monitored vaccine program, the disease remains a significant global health issue, requiring the use of antiviral drugs like oseltamivir (Tamiflu). A significant problem in controlling the spread of influenza is the emergence of oseltamivir-resistant strains.

To address this problem, Dr. Jeremy Wulff is taking a collaborative approach to develop potent new influenza virus inhibitors. With Professor Martin Boulanger's group at the University of Victoria Department of Biochemistry, Dr. Wulff has developed a new class of antiviral agents that function by a similar mechanism to oseltamivir. His research group is working to further improve the efficacy of these agents through structural and kinetic means. Finally, Dr. Wulff will test the potency of the new anti-influenza compounds in collaboration with Dr. Terrence Tumpey, from the U.S. Centers for Disease Control in Atlanta.

Identifying and developing new drugs to fight oseltamivir-resistant influenza is anticipated to have wide-reaching impacts on global health. In addition to creation of new influenza drugs, Dr. Wulff’s research interests include the development of novel methodologies for the synthesis of complex molecules, and the invention of new kinds of inhibitors that specifically block interactions between certain proteins involved in pancreatic cancer and HIV.

Investigating the relationship between residential stability, physical and mental health, and quality of life in homeless and vulnerably housed individuals: A multi-site longitudinal study

An increasingly large number of individuals are facing homelessness and inadequate housing (i.e. living in a shelter, on the street or other places not intended for human habitation) in Canada. Annually, it is estimated that 150,000 to 300,000 individuals experience homelessness across the country. In addition, a much larger number of individuals are vulnerably housed (i.e. individuals with low or moderate income who spend more than 50 percent of their income on housing and are at risk of becoming homeless). Housing is a significant determinant of health. Compared to the general population, homeless and vulnerably housed individuals (HVHIs) have been found to be at a substantially increased risk for physical and mental illness, substance use, injuries, assaults and mortality. Furthermore, HVHIs are socially marginalized and frequently experience barriers to health care and social services. Dr. Anne Gadermann will be examining the dynamics of homelessness and housing vulnerability over time, risk and protective factors associated with onset and exiting of homelessness, and whether changes in housing status are associated with changes in physical and mental health status and quality of life. To conduct her research, Dr. Gadermann will be analyzing data from the Health and Housing in Transition study, a longitudinal multi-site cohort study of HVHIs. In this study, a representative sample of more than 1,100 HVHIs has been interviewed annually over a three-year period in Vancouver, Ottawa and Toronto. At each time point, the interview surveys assessed a wide number of variables, including demographic characteristics, housing history and quality of living conditions, physical and mental health status, family history, substance use problems, quality of life, social support, risk behaviours, health care and social service utilization, contact with the legal system, and life events. Furthermore, the interview data have been linked to health insurance databases to provide information on respondents’ health care utilization. Given the increase of homelessness and vulnerable housing in Canada, there is a greater need and demand for research evidence that can complement and expand existing policies, services and programs. The proposed research project is uniquely situated to provide such research evidence, and a special focus will be given to the dissemination of the findings in order to maximize the impact of the research findings on public policies, services and programs related to housing and health.

Pathophysiological contributions of T-type calcium channel variation towards thalamocortical network hyperexcitability and absence epilepsy

More than 50 million people worldwide suffer from epilepsy. Approximately 90 percent of those treated with current drugs experience significant side effects, and around 30 percent do not respond to current medical treatments at all. Therefore, significantly better treatments are required to improve the quality of life for epilepsy sufferers in Canada and worldwide. To achieve this, a far greater understanding of how the brain works both normally and during seizures is necessary.

Epilepsy is a difficult disorder to study in humans; however, in the 1980s, a strain of rats that naturally suffer from a type of seizure very similar to the human condition and involving the same brain regions was identified. These rats are extremely useful in helping us understand the causes of epilepsy in humans and test new drugs being developed to treat epilepsy. Two years ago, Dr. Stuart Cain’s research characterized a newly discovered genetic mutation in the epileptic rat strain responsible for a large portion of seizures. Epileptic seizures can be caused by changes in the way certain brain nerve cell proteins, known as "calcium channels," conduct electricity — the mutation characterized by Dr. Cain alters the way in which a specific type of calcium channel conducts electrical signaling. This was significant as these particular calcium channels are able to generate patterns of electrical pulses, known as “firing patterns,” predicted to contribute to epileptic seizures.

Dr. Cain’s research project aims to determine how the calcium channel mutation alters communication between nerve cells and affects different firing patterns. His laboratory is the only site in North America currently studying the epileptic rat strain. Understanding what causes the firing properties of epileptic nerves to change during seizures should allow the design of new drug treatments with the ability to block these changes directly, and to also reduce side effects compared to many of the broad-target drugs currently used clinically.

Analysis of the influence of retroelements on activation of oncogenes in primary human lymphomas using high-throughput sequencing

Endogenous retroviruses (ERVs) are viral DNA sequences that have repeatedly inserted themselves through the course of primate evolution and in turn become an integral part of the human genome. The human genome contains more than 200 families of ERVs, which together comprise approximately 8 percent of our chromosomal DNA. A growing body of evidence indicates that ERVs have been a major player in molecular evolution and continue to impact the mammalian genome by acting as insertional mutagens, inducing DNA rearrangements and altering gene regulation. Given the potential for harmful effects, it is not surprising that mammals have evolved multiple lines of defense against these endogenous retroviruses, such as modifying the DNA or chromatin structure to prevent the genes from being expressed. In theory, if the ERVs are de-repressed, they could become active and then cause disruptive events leading to cancer. Although the structure, function and impact of human ERVs (HERVs) on the human genome has been studied in detail, their potential contribution to cancer has not been systematically examined. Dr. Mohammed Mahdi Karimi will be applying his experience in bioinformatics methods and high-throughput epigenetic analyses to study HERV families in human cancers. He will examine gene expression patterns and different types of epigenetic modifications, including histone modifications and DNA methylation, in primary lymphocytes isolated from lymphoma patients as well as in cell lines. By identifying the epigenetic changes in the genomes of HERV families, he hopes to determine how abnormal gene expression leads to the development of human lymphomas. Dr. Karimi expects that the results from this initial analysis will reveal genes that are misregulated in cancer as a result of the de-repression of HERVs, and this misregulation will be reflected in changes to the DNA or chromatin modification. The ultimate goal of Dr. Karimi’s research is to identify molecular or epigenetic pathways that are perturbed in different types of human lymphomas, which in turn may potentially be targeted with new therapeutic strategies.

Generation of a humanized mouse xenotransplant model of myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow. MDS originate when a stem cell, from which all other blood cells originate, becomes mutated and then overgrows and crowds out other cells. This results in reduced numbers of red cells (anemia), white cells (leukopenia) and platelets (thrombocytopenia) circulating in the blood. As the disease progresses, bone marrow may completely fail to produce normal cells, and the myelodysplastic stem cell may develop into cancer, Acute myeloid leukemia (AML). The exact molecular causes for MDS are unknown; however, a common feature of MDS is chromosomal abnormality, the loss of the long arm (q) of the chromosome 5 being one of the most common in a subtype of MDS called 5q- syndrome. This lost region of 5q likely harbors several important genes, which may prevent MDS.

Dr. Joanna Wegrzyn Woltosz's research project will decipher the molecular mechanism of the disease and identify targets of a new drug (lenalidomide) currently used in MDS treatment. She is studying two important factors that are located on the 5q arm and are involved in the development of MDS (1) the RPS14 gene, which is thought to be responsible for the anemia seen in MDS patients, and (2) microRNAs, whose loss allows the abnormal MDS stem cells to survive and grow more than the other bone marrow cells. Since lenalidomide reverses symptoms resulting from loss of the microRNAs, she will also study whether lenalidomide increases the expression of these microRNAs. Currently, the only treatment for MDS is high-dose chemotherapy with stem cell transplantation, which is risky and challenging for patients to endure.

The information Dr. Wegrzyn Woltosz expects to obtain from this study will not only help to better understand the molecular mechanism underlying MDS, but will suggest novel steps towards the development of better therapies that will improve treatment and quality of life and increase survival for MDS patients.

Endothelial cell regulation of T cell responses

Organ transplantation is a life-saving procedure for many individuals. Unfortunately, the long-term success of this procedure is compromised by the rejection of the transplanted organ(s) by the recipient's immune system. T cells are specialized cells of the immune system that protect against infections but that recognize and damage transplanted organs. Understanding how T cell responses are controlled will help to develop new methods to increase the long-term and specific acceptance of transplanted organs.

Dr. Jonathan Choy's research is focused on understanding how T cell survival and persistence is regulated and how these processes contribute to organ transplant rejection. By understanding this, Dr. Choy intends to find new ways of controlling the immune response against transplanted organs. Preventing rejection will improve outcomes for the approximately 2,000 Canadians who receive solid organ transplants each year, as well as for the many Canadians who are already living with transplants.