Balshaw R.,University of British Columbia |
Cohen-Freue G.V.,University of British Columbia |
Imai C.,St Pauls Hospital |
Kaan A.,St Pauls Hospital |
And 4 more authors.
Journal of Heart and Lung Transplantation | Year: 2013
Background: Acute rejection in cardiac transplant patients remains a contributory factor to limited survival of implanted hearts. Currently, there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplant acute cellular rejection. Such a development would be of great value in personalizing immunosuppressive treatment. Methods: Recipient age, donor age, cold ischemic time, warm ischemic time, panel-reactive antibody, gender mismatch, blood type mismatch and human leukocyte antigens (HLA-A, -B and -DR) mismatch between recipients and donors were tested in 53 heart transplant patients for their power to predict post-transplant acute cellular rejection. Donor transplant biopsy and recipient pre-transplant blood were also examined for the presence of genomic biomarkers in 7 rejection and 11 non-rejection patients, using non-targeted data mining techniques. Results: The biomarker based on the 8 clinical variables had an area under the receiver operating characteristic curve (AUC) of 0.53. The pre-transplant recipient blood gene-based panel did not yield better performance, but the donor heart tissue gene-based panel had an AUC = 0.78. A combination of 25 probe sets from the transplant donor biopsy and 18 probe sets from the pre-transplant recipient whole blood had an AUC = 0.90. Biologic pathways implicated include VEGF- and EGFR-signaling, and MAPK. Conclusions: Based on this study, the best predictive biomarker panel contains genes from recipient whole blood and donor myocardial tissue. This panel provides clinically relevant prediction power and, if validated, may personalize immunosuppressive treatment and rejection monitoring. © 2013 International Society for Heart and Lung Transplantation.
Zhang T.,University of British Columbia |
Zhang T.,BC Childrens Hospital |
Zhang T.,Child and Family Research Institute |
Smith M.A.,BC Childrens Hospital |
And 9 more authors.
European Journal of Clinical Pharmacology | Year: 2013
Background: Population-based drug utilization databases that comprehensively capture an entire population's drug dispensing are scarce resources for epidemiological studies. This study aimed to examine the prescription-dispensing rates in children in British Columbia (BC) and describe the differences in the dispensing of medications in BC versus children in the United States (US) and Europe. Methods: The study population was children aged 0-17 years in BC (n = 855,541). Children with at least one prescription dispensed in 2007 were identified using the provincial outpatient prescription dispensing database. All prescriptions were grouped on the basis of the Anatomical Therapeutic Chemical (ATC) classification system. Prevalence of drug dispensing was calculated in each age group, gender, and therapeutic class. Results: Fifty-five percent of BC children were dispensed at least one prescription in 2007. Antibacterials for systemic use, dermatological corticosteroids, and drugs for obstructive airway diseases were commonly dispensed in each age group. The percentage of children who received psychoanaleptics was two to five times higher than rates reported in European countries, but 30% lower than rates reported in the US. Conclusions: Half of the BC population <18 years received at least one prescription in 2007. Significant variations in drug dispensing were highlighted between BC, the US, and Europe. Future studies are needed to examine the outcomes of the prescribing in terms of benefit and harm. A variety of factors (e.g., disease prevalence rates, drug prescribing preferences) are likely to contribute to disparate dispensing of specific drug classes and should be principal factors in the investigation. © 2012 Springer-Verlag.
Putko B.N.,University of Alberta |
Putko B.N.,Mazankowski Alberta Heart Institute |
Yogasundaram H.,University of Alberta |
Yogasundaram H.,Mazankowski Alberta Heart Institute |
And 8 more authors.
European Journal of Heart Failure | Year: 2015
Aims Anderson-Fabry disease (AFD) is an important X-linked metabolic disease resulting in progressive end-organ involvement, with cardiac disease being the dominant determinant of survival in a gender-dependent manner. Recent epidemiological screening for AFD suggests the prevalence is much higher than previously recognized, with estimates of 1:3000. Our aim was to discover novel plasma biomarker signatures in adult patients with AFD. Methods and results We used an unbiased proteomic screening approach to discover novel plasma biomarker signatures. In the discovery cohort of 46 subjects, 14 healthy controls and 32 patients with AFD, we used a mass spectrometry iTRAQ proteomic approach followed by multiple reaction monitoring (MRM) assays to identify biomarkers. Of the 38 protein groups discovered by iTRAQ, 18 already had existing MRM assays. Based on MRM, we identified an eight-protein biomarker panel (22 kDa protein, afamin, α1 antichymotrypsin, apolipoprotein E, β-Ala His dipeptidase, haemoglobin α-2, isoform 1 of sex hormone-binding globulin, and peroxiredoxin 2) that was very specific and sensitive for male AFD patients. In female AFD patients, we identified a nine-marker panel of proteins with only three proteins, apolipoprotein E, haemoglobin α-2, and peroxiredoxin 2, common to both genders, suggesting a gender-specific alteration in plasma biomarkers in patients with AFD. The biomarkers were validated in plasma samples from 48 subjects using MRM, and they performed inferiorly in patients with heart failure. Conclusions We have identified gender-specific plasma protein biomarker panels that are specific and sensitive for the AFD phenotype. The gender-specific panels offer important insight into potential differences in pathophysiology and prognosis between males and females with AFD. © 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.
Cohen Freue G.V.,University of British Columbia |
Meredith A.,University of British Columbia |
Smith D.,University of Victoria |
Bergman A.,Immunity and Infection Research Center |
And 14 more authors.
PLoS Computational Biology | Year: 2013
Recent technical advances in the field of quantitative proteomics have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. However, inherent challenges have limited the successful translation of candidate biomarkers into clinical use, thus highlighting the need for a robust analytical methodology to transition from biomarker discovery to clinical implementation. We have developed an end-to-end computational proteomic pipeline for biomarkers studies. At the discovery stage, the pipeline emphasizes different aspects of experimental design, appropriate statistical methodologies, and quality assessment of results. At the validation stage, the pipeline focuses on the migration of the results to a platform appropriate for external validation, and the development of a classifier score based on corroborated protein biomarkers. At the last stage towards clinical implementation, the main aims are to develop and validate an assay suitable for clinical deployment, and to calibrate the biomarker classifier using the developed assay. The proposed pipeline was applied to a biomarker study in cardiac transplantation aimed at developing a minimally invasive clinical test to monitor acute rejection. Starting with an untargeted screening of the human plasma proteome, five candidate biomarker proteins were identified. Rejection-regulated proteins reflect cellular and humoral immune responses, acute phase inflammatory pathways, and lipid metabolism biological processes. A multiplex multiple reaction monitoring mass-spectrometry (MRM-MS) assay was developed for the five candidate biomarkers and validated by enzyme-linked immune-sorbent (ELISA) and immunonephelometric assays (INA). A classifier score based on corroborated proteins demonstrated that the developed MRM-MS assay provides an appropriate methodology for an external validation, which is still in progress. Plasma proteomic biomarkers of acute cardiac rejection may offer a relevant post-transplant monitoring tool to effectively guide clinical care. The proposed computational pipeline is highly applicable to a wide range of biomarker proteomic studies. © 2013 Cohen Freue et al.
Russell J.A.,James Hogg Research Center |
Russell J.A.,University of British Columbia |
Russell J.A.,Saint Pauls Hospital |
Fjell C.,James Hogg Research Center |
And 11 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013
Rationale: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock. Objectives: Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and norepinephrine on plasma cytokine levels in septic shock. Methods:We studied 394 patients in a randomized, controlled trial of vasopressin versus norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus norepinephrine-induced changes in cytokine levels over 24 hours. Measurements and Main Results: A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P , 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with norepinephrine (P = 0.037). In less severe septic shock, the difference in plasma cytokine reduction over 24 hours between survivors and nonsurvivors was less pronounced than that seen inmoresevere septic shock. Furthermore, vasopressin decreased interferon-inducible protein 10 and granulocyte colony- stimulating factormore than did norepinephrine in less severe septic shock, whereas vasopressin decreased granulocyte-macrophage colony-stimulating factor in patients who had more severe shock. Conclusions: Survivors of septic shock had greater decreases of cytokines, chemokines and growth factors in early septic shock. Vasopressin decreased 24-hour plasma cytokine levels more than did norepinephrine. The vasopressin-associated decrease of cytokines differed according to severity of shock. Clinical trial registeredwithwww.controlled-trials.com (ISRCTN94845869). © 2013 by the American Thoracic Society.
Leung J.M.,James Hogg Research Center |
Liu J.C.,James Hogg Research Center |
Mtambo A.,St Pauls Hospital |
Ngan D.,James Hogg Research Center |
And 16 more authors.
AIDS Patient Care and STDs | Year: 2014
The increased longevity afforded by combination antiretroviral therapy in developed countries has led to an increased concern regarding senescence-related diseases in patients with human immunodeficiency virus (HIV) infection. Previous epidemiologic analyses have demonstrated an increased risk of chronic obstructive pulmonary disease, as well as a significant burden of respiratory symptoms in HIV-infected patients. We performed the St. George's Respiratory Questionnaire (SGRQ) in 199 HIV-positive men, and determined the predominant factors contributing to poor respiratory-related health status. In univariate analyses, worse SGRQ scores were associated with respiratory-related variables such as greater smoking pack-year history (p=0.028), lower forced expiratory volume in 1 second (FEV1) (p<0.001), and worse emphysema severity as quantified by computed tomographic imaging (p=0.017). In addition, HIV-specific variables, such as a history of plasma viral load >100,000 copies/mL (p=0.043), lower nadir CD4 cell count (p=0.040), and current CD4 cell count ≤350 cells/μL (p=0.005), as well as elevated levels of inflammatory markers, specifically plasma interleukin (IL)-6 (p=0.002) and alpha-1 antitrypsin (p=0.005) were also associated with worse SGRQ scores. In a multiple regression model, FEV1, current CD4 count ≤350 cells/μL, and IL-6 levels remained significant contributors to reduced respiratory-related health status. HIV disease activity as measured by HIV-related immunosuppression in conjunction with the triggering of key inflammatory pathways may be important determinants of worse respiratory health status among HIV-infected individuals. Limitations of this analysis include the absence of available echocardiograms, diffusion capacity and lung volume testing, and an all-male cohort due to the demographics of the clinic population. © 2014, Mary Ann Liebert, Inc.