Patrick S Parfrey

Newfoundland and Labrador Centre for Health Information, Saint John's, Newfoundland and Labrador, Canada

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Publications (337)2470.23 Total impact

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    ABSTRACT: -Patients with kidney disease have disordered bone and mineral metabolism including elevated serum concentrations of fibroblast growth factor 23 (FGF23). The latter are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. -This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (iPTH ≥ 300 pg/mL). The primary study end point was time to death or the first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 (67%) patients with samples at both baseline and week 20. The results demonstrated a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite endpoint (relative hazard (HR) 0.82; 95% confidence interval (95% CI) 0.69, 0.98), cardiovascular mortality (HR 0.66; 0.50, 0.87), sudden cardiac death (HR 0.57; 0.37, 0.86), and heart failure (HR 0.69; 0.48, 0.99). -Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events. Clinical Trial Registration Information-ClinicalTrials.gov. Identifier: NCT00345839.
    Circulation 06/2015; 132(1). DOI:10.1161/CIRCULATIONAHA.114.013876 · 14.95 Impact Factor
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    ABSTRACT: Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.Journal of Human Hypertension advance online publication, 4 June 2015; doi:10.1038/jhh.2015.56.
    Journal of human hypertension 06/2015; DOI:10.1038/jhh.2015.56 · 2.69 Impact Factor
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    ABSTRACT: Mitochondrion is a small organelle inside the eukaryotic cells. It has its own genome (mtDNA) and encodes for proteins that are critical for energy production and cellular metabolism. Mitochondrial dysfunctions have been implicated in cancer progression and may be related to poor prognosis in cancer patients. In this study we hypothesized that genetic variations in mtDNA are associated with clinical outcome in colorectal cancer patients. We tested the associations of six mtDNA polymorphisms [MitoT479C, MitoT491C, MitoT10035C, MitoA13781G, 10398 (A/G), and 16189 (T/C)] and the mtDNA copy number change with overall survival (OS) and disease-free survival (DFS) times. Two mtDNA polymorphisms were genotyped using the TaqMan(®) SNP genotyping technique and the genotypes for the remaining four mtDNA polymorphisms were obtained by the Illumina(®) HumanOmni1-Quad genome wide SNP genotyping platform in 536 patients. The mtDNA copy number change (in tumor tissues with respect to non-tumor tissues) was estimated using the quantitative real time polymerase chain reaction for 274 patients. Associations of these mtDNA variations with OS and DFS were tested using the Cox regression method. In both univariate and multivariable analyses, none of the six mtDNA polymorphisms were associated with OS or DFS. 39.6 and 60.4% of the patients had increased and decreased mtDNA copy number in their tumor tissues when compared to their non-tumor rectum or colon tissues, respectively. However, in contrast to previous findings, the change in the mtDNA copy number was associated with neither OS nor DFS in our patient cohort. Our results suggest that the mitochondrial genetic markers investigated in this study are not associated with outcome in colorectal cancer.
    BMC Research Notes 06/2015; 8(1):272. DOI:10.1186/s13104-015-1250-5
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    ABSTRACT: The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD. TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level ≤11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes. Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics. Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors. Copyright © 2015 Elsevier Inc. All rights reserved.
    American Heart Journal 05/2015; 170(2). DOI:10.1016/j.ahj.2015.05.008 · 4.56 Impact Factor
  • Jürgen Floege · Yumi Kubo · Anna Floege · Glenn M Chertow · Patrick S Parfrey
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    ABSTRACT: Uncontrolled secondary hyperparathyroidism (sHPT) in patients with ESRD is a risk factor for calcific uremic arteriolopathy (CUA; calciphylaxis). Adverse event reports collected during the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial were used to determine the frequency of CUA in patients receiving hemodialysis who had moderate to severe sHPT, as well as the effects of cinacalcet versus placebo. CUA events were collected while patients were receiving the study drug. Among the 3861 trial patients who received at least one dose of the study drug, 18 patients randomly assigned to placebo and six assigned to cinacalcet developed CUA (unadjusted relative hazard, 0.31; 95% confidence interval [95% CI], 0.13 to 0.79; P=0.014). Corresponding cumulative event rates (95% CI) at year 4 were 0.011% (0.006% to 0.018%) and 0.005% (0.002% to 0.010%). By multivariable analysis, other factors associated with CUA included female sex, higher body mass index, higher diastolic BP, and history of dyslipidemia or parathyroidectomy. Median (10%, 90% percentile) plasma parathyroid hormone concentrations proximal to the report of CUA were 796 (225, 2093) pg/ml and 410 (71, 4957) pg/ml in patients randomly assigned to placebo and cinacalcet, respectively. Active use of vitamin K antagonists was recorded in 11 of 24 patients with CUA, nine randomly assigned to placebo, and two to cinacalcet, in contrast to 5%-7% at any one time point in patients in whom CUA was not reported. Cinacalcet appeared to reduce the incidence of CUA in hemodialysis recipients who have moderate to severe sHPT. Copyright © 2015 by the American Society of Nephrology.
    Clinical Journal of the American Society of Nephrology 04/2015; 10(5). DOI:10.2215/CJN.10221014 · 5.25 Impact Factor
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    ABSTRACT: Intention-to-treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long-term outcomes study where non-adherence to study drug is substantial, the on-treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double-blind, placebo-controlled, event-driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre-specified sensitivity analyses were performed to assess the impact of non-adherence on the estimated effect of cinacalcet. These analyses included lag-censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag-censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on-treatment effect when substantial non-adherence to study drug is expected or observed. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Pharmaceutical Statistics 04/2015; 14(3). DOI:10.1002/pst.1680 · 1.10 Impact Factor
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    ABSTRACT: Hemodialysis (HD) is the main form of renal replacement therapy for many patients with end-stage renal disease. The purpose of this research is to assess reliability and validity of the Patient's Perception of Hemodialysis Scale. Using a cross-sectional design and a convenient sample (n = 236), psychometric properties of the PPHS were examined. Validity was assessed using factor analysis and Pearson's correlation. Reliability was determined using Cronbach's alpha and test-retest stability (n = 30). Validity and reliability was supported. Examination of the PPHS provides evidence that it is a valid and reliable instrument for measuring disease-specific concerns with the HD patients, assessing how people experience life, and identifying ways in which people interpret the meaning of their physical and psychosocial health and adaptation to life on HD.
    Journal of Nursing Measurement 04/2015; 23(1). DOI:10.1891/1061-3749.23.1.72
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    ABSTRACT: In this study we performed genome-wide association studies to identify candidate SNPs that may predict the risk of disease outcome in colorectal cancer. Patient cohort consisted of 505 unrelated patients with Caucasian ancestry. Germline DNA samples were genotyped using the Illumina® human Omni-1quad SNP chip. Associations of SNPs with overall and disease free survivals were examined primarily for 431 patients with microsatellite instability-low (MSI-L) or stable (MSS) colorectal tumors using Cox proportional hazards method adjusting for clinical covariates. Bootstrap method was applied for internal validation of results. As exploratory analyses, association analyses for the colon (n = 334) and rectal (n = 171) cancer patients were also performed. As a result, there was no SNP that reached the genomewide significance levels (p < 5x10(-8)) in any of the analyses. A small number of genetic markers (n = 10) showed nominal associations (p <10(-6)) for MSS/MSI-L, colon, or rectal cancer patient groups. These markers were located in two non-coding RNA genes or intergenic regions and none were amino acid substituting polymorphisms. Bootstrap analysis for the MSS/MSI-L cohort data suggested the robustness of the observed nominal associations. Likely due to small number of patients, our study did not identify an acceptable level of association of SNPs with outcome in MSS/MSI-L, colon, or rectal cancer patients. A number of SNPs with sub-optimal p-values were, however, identified; these loci may be promising and examined in other larger-sized patient cohorts.
    03/2015; 3(1):6. DOI:10.1186/s40364-015-0031-6
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    ABSTRACT: The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients. Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone. Copyright © 2015 by the American Society of Nephrology.
    Clinical Journal of the American Society of Nephrology 02/2015; 10(5). DOI:10.2215/CJN.07730814 · 5.25 Impact Factor
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    ABSTRACT: The relationship between major dietary patterns and colorectal cancer (CRC) in other populations largely remains consistent across studies. The objective of the present study is to assess if dietary patterns are associated with the risk of CRC in the population of Newfoundland and Labrador (NL). Data from a population based case-control study in the province of NL were analyzed, including 506 CRC patients (306 men and 200 women) and 673 controls (400 men and 273 women), aged 20-74 years. Dietary habits were assessed by a 169-item food frequency questionnaire (FFQ). Logistic regression analyses were performed to investigate the association between dietary patterns and the CRC risk. Three major dietary patterns were derived using factor analysis, namely a Meat-diet pattern, a Plant-based diet pattern and a Sugary-diet pattern. In combination the three dietary patterns explained 74% of the total variance in food intake. Results suggest that the Meat-diet and the Sugary-diet increased the risk of CRC with corresponding odds ratios (ORs) of 1.84 (95% CI: 1.19-2.86) and 2.26 (95% CI: 1.39-3.66) for people in the highest intake quintile compared to those in the lowest. Whereas plant-based diet pattern decreases the risk of CRC with a corresponding OR of 0.55 (95% CI: 0.35-0.87). Even though odds ratios (ORs) were not always statistically significant, largely similar associations across three cancer sites were found: the proximal colon, the distal colon, and the rectum. The finding that Meat-diet/Sugary-diet patterns increased and Plant-based diet pattern decreased the risk of CRC would guide the promotion of healthy eating for primary prevention of CRC in this population.
    Nutrition Journal 01/2015; 14(1):8. DOI:10.1186/1475-2891-14-8 · 2.64 Impact Factor
  • Robert N Foley · Patrick S Parfrey
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    ABSTRACT: Quality-of-life (QoL) outcomes are important elements of randomized controlled trials. The instruments for measurement of QoL vary but usually multiple comparisons are possible, a concern that can be offset by prespecifying the outcomes of interest. Missing data may threaten the validity of QoL assessments in trials. Therefore familiarity with the strategies used to account for missing data is necessary. Measures that incorporate both survival and QoL are helpful for treatment decisions. The definition of minimal clinically important differences in QoL scores is important and often derived using inadequate methods.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:261-72. DOI:10.1007/978-1-4939-2428-8_15 · 1.29 Impact Factor
  • Susan Stuckless · Patrick S Parfrey
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    ABSTRACT: Clinical epidemiological research in genetic diseases entails assessment of phenotypes, the burden and etiology of disease, and the efficacy of preventive measures or treatments in populations. In all areas, the main focus is to describe the relationship between exposure and outcome and to determine one of the following: prevalence, incidence, cause, prognosis, or effect of treatment. The accuracy of these conclusions is determined by the validity of the study. Validity is determined by addressing potential biases and possible confounders that may be responsible for the observed association. Therefore, it is important to understand the types of bias that exist and also to be able to assess their impact on the magnitude and direction of the observed effect. The following chapter reviews the epidemiological concepts of selection bias, information bias, and confounding and discusses ways in which these sources of bias can be minimized.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:333-48. DOI:10.1007/978-1-4939-2428-8_20 · 1.29 Impact Factor
  • Patrick S Parfrey
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    ABSTRACT: The intention-to-treat analysis is the gold standard for evaluating efficacy in a randomized controlled trial. However, when non-adherence to randomized treatments is high, the actual treatment effect may be underestimated. The impact of drop-out from the intervention group or drop-in to the control group may be controlled by trial design, increasing the sample size, effective study execution, and a prespecified analytical plan to take contamination into account.These analyses may include censoring at time of co-interventions associated with stopping treatment, lag censoring which allows an additional period after discontinuation of study treatment to account for residual treatment effects, inverse probability of censoring weights (IPCW), accelerated failure time models, and contamination adjusted intent-to-treat analysis. These methods are particularly useful in assessing the "prescribed efficacy" of the study treatment, which can aid clinical decision-making.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:249-59. DOI:10.1007/978-1-4939-2428-8_14 · 1.29 Impact Factor
  • Pietro Ravani · Brendan J Barrett · Patrick S Parfrey
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    ABSTRACT: Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals).
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:71-92. DOI:10.1007/978-1-4939-2428-8_5 · 1.29 Impact Factor
  • Pietro Ravani · Brendan J Barrett · Patrick S Parfrey
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    ABSTRACT: In longitudinal studies the relationship between exposure and disease can be measured once or multiple times while participants are monitored over time. Traditional regression techniques are used to model outcome data when each epidemiological unit is observed once. These models include generalized linear models for quantitative continuous, discrete, or qualitative outcome responses, and models for time-to-event data. When data come from the same subjects or group of subjects, observations are not independent and the underlying correlation needs to be addressed in the analysis. In these circumstances extended models are necessary to handle complexities related to clustered data, and repeated measurements of time-varying predictors and/or outcomes.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:93-131. DOI:10.1007/978-1-4939-2428-8_6 · 1.29 Impact Factor
  • Bryan M Curtis · Brendan J Barrett · Patrick S Parfrey
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    ABSTRACT: Today's clinical practice relies on the application of well-designed clinical research, the gold standard test of an intervention being the randomized controlled trial. Principles of the randomized control trial include emphasis on the principal research question, randomization, blinding; definitions of outcome measures, of inclusion and exclusion criteria, and of comorbid and confounding factors; enrolling an adequate sample size; planning data management and analysis; preventing challenges to trial integrity such as drop-out, drop-in, and bias. The application of pretrial planning is stressed to ensure the proper application of epidemiological principles resulting in clinical studies that are feasible and generalizable. In addition, funding strategies and trial team composition are discussed.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:159-75. DOI:10.1007/978-1-4939-2428-8_9 · 1.29 Impact Factor
  • Elizabeth Hatfield · Elizabeth Dicks · Patrick S Parfrey
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    ABSTRACT: Large integrated multidisciplinary teams have become recognized as an efficient means by which to drive innovation and discovery in clinical research. This chapter describes how to plan, budget and fund these large studies and execute the studies with well-designed governance and monitoring protocols in place, to efficiently manage the large, often dispersed teams involved. Sources of funding are identified, budget development, justification, reporting, financial governance and accountability are described, in addition to the creation and management of the multidisciplinary team that will implement the research plan.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1281:273-86. DOI:10.1007/978-1-4939-2428-8_16 · 1.29 Impact Factor
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    ABSTRACT: Several published studies identified associations of a number of polymorphisms with a variety of survival outcomes in colorectal cancer. In this study, we aimed to explore 102 previously reported common genetic polymorphisms and their associations with overall survival (OS) and disease-free survival (DFS) in a colorectal cancer patient cohort from Newfoundland . Genotypes were obtained using a genomewide SNP genotyping platform. For each polymorphism, the best possible genetic model was estimated for both overall survival and disease-free survival using a previously published approach. These SNPs were then analyzed under their genetic models by Cox regression method. Correction for multiple comparisons was performed by the False Discovery Rate (FDR) method. Univariate analysis results showed that RRM1-rs12806698, IFNGR1-rs1327474, DDX20-rs197412, and PTGS2-rs5275 polymorphisms were nominally associated with OS or DFS . In stage-adjusted analysis, the nominal associations of DDX20-rs197412, PTGS2-rs5275, and HSPA5-rs391957 with DFS were detected. However, after FDR correction none of these polymorphisms remained significantly associated with the survival outcomes. We conclude that polymorphisms investigated in this study are not associated with OS or DFS in our colorectal cancer patient cohort.
    01/2015; 2015:1-9. DOI:10.1155/2015/968743
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    ABSTRACT: Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%. Copyright © 2014 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 12/2014; 26(6). DOI:10.1681/ASN.2014040414 · 9.47 Impact Factor
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    ABSTRACT: Colorectal cancer is a common malignancy. Identification of genetic prognostic markers may help prognostic estimations in colorectal cancer. Genes that regulate response to hypoxia and other genes that are regulated under the hypoxic conditions have been shown to play roles in cancer progression. In this study, we hypothesized that genetic variations in the hypoxia pathway genes were associated with the risk of outcome in colorectal cancer patients. This study was performed in two phases. In the first phase, 49 SNPs from six hypoxia pathway genes (HIF1A, HIF1B, HIF2A, LOX, MIF and CXCL12) in 272 colorectal cancer patients were analyzed. In the second phase, 77 SNPs from seven hypoxia pathway genes (HIF1A, HIF1B, HIF2A, HIF2B, HIF3A, LOX and CXCL12) were analyzed in an additional cohort of 535 patients. Kaplan Meier, Cox univariate and multivariable regression analyses were performed to analyze the relationship between the SNPs and overall survival (OS), disease free survival (DFS) or disease specific survival (DSS). Since this was a hypothesis-generating study, no correction for multiple testing was applied. In phase I, one SNP (HIF2A rs11125070) was found to be associated with DFS in multivariable analysis; yet association of a proxy polymorphism (HIF2A rs4953342) was not detected in the phase II patient cohort. In phase II, associations of two SNPs (HIF2A rs4953352 and HIF2B rs12593988) were significant in both OS and DFS multivariable analyses. However, association of HIF2A rs4953352 was not replicated in the phase I cohort using a proxy SNP (HIF2A rs6706003). Overall, our study did not find a convincing evidence of association of the investigated polymorphisms with the disease outcomes in colorectal cancer.
    PLoS ONE 11/2014; 9(11):e113513. DOI:10.1371/journal.pone.0113513 · 3.23 Impact Factor

Publication Stats

22k Citations
2,470.23 Total Impact Points

Institutions

  • 2015
    • Newfoundland and Labrador Centre for Health Information
      Saint John's, Newfoundland and Labrador, Canada
  • 1986–2015
    • Memorial University of Newfoundland
      • • Faculty of Medicine
      • • Division of Nephrology
      Saint John's, Newfoundland and Labrador, Canada
  • 2012–2014
    • Health Canada
      • Health Sciences Center
      Ottawa, Ontario, Canada
  • 2010
    • SickKids
      • Program in Genetics and Genome Biology
      Toronto, Ontario, Canada
  • 2009
    • Azienda Ospedaliera di Cremona
      Cremona, Lombardy, Italy
    • McMaster University
      • Department of Clinical Epidemiology and Biostatistics
      Hamilton, Ontario, Canada
  • 2007
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2004
    • Washington University in St. Louis
      • Department of Genetics
      Saint Louis, MO, United States
  • 2002
    • University of Birmingham
      Birmingham, England, United Kingdom
    • University of Manitoba
      Winnipeg, Manitoba, Canada
  • 1999
    • Boston University
      • Section of Preventive Medicine and Epidemiology
      Boston, Massachusetts, United States
  • 1998
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1996
    • Florida Memorial University
      Saint John, Indiana, United States
  • 1995
    • Dalhousie University
      • Department of Medicine
      Halifax, Nova Scotia, Canada
  • 1985–1986
    • McGill University
      Montréal, Quebec, Canada