Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

BACKGROUND: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). METHODS: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. RESULTS: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). CONCLUSIONS: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Structured learning in time-dependent Cox models.

Cox models with time-dependent coefficients and covariates are widely used in survival analysis. In high-dimensional settings, sparse regularization techniques are employed for variable selection, but existing methods for time-dependent Cox models lack flexibility in enforcing specific sparsity patterns (ie, covariate structures). We propose a flexible framework for variable selection in time-dependent Cox models, accommodating complex selection rules. Our method can adapt to arbitrary grouping structures, including interaction selection, temporal, spatial, tree, and directed acyclic graph structures. It achieves accurate estimation with low false alarm rates. We develop the sox package, implementing a network flow algorithm for efficiently solving models with complex covariate structures. sox offers a user-friendly interface for specifying grouping structures and delivers fast computation. Through examples, including a case study on identifying predictors of time to all-cause death in atrial fibrillation patients, we demonstrate the practical application of our method with specific selection rules.

Androgen Deprivation Therapy and Risk of Cardiovascular Disease in Patients With Prostate Cancer Based on Existence of Cardiovascular Risk.

BACKGROUND: Controversy exists regarding the risk of cardiovascular disease (CVD) associated with androgen deprivation therapy (ADT) in patients with prostate cancer. We sought to evaluate the association between gonadotropin-releasing hormone (GnRH) agonists versus GnRH antagonist and the risk of CVD in patients with prostate cancer with or without prior CVD. PATIENTS AND METHODS: Using administrative databases from Quebec, Canada, we identified first-time GnRH agonists and antagonist (degarelix) users between January 2012 and June 2016. Follow-up ended at the earliest of the following: first CVD event (myocardial infarction [MI], stroke, ischemic heart disease [IHD], arrhythmia, and heart failure [HF]); switch of GnRH group; death; or December 31, 2016. Inverse probability of treatment weighting (IPTW) based on the propensity score was used to control for potential confounding. IPTW-Cox proportional hazards model accounting for competing risks was used to evaluate the association of interest. RESULTS: Among 10,785 patients identified, 10,201 and 584 were on GnRH agonists and antagonist, respectively. Median age was 75 years (interquartile range, 69-81 years) for both groups. A total of 4,152 (40.7%) men in the GnRH agonists group and 281 (48.1%) men in the GnRH antagonist group had CVD in the 3-year period prior to ADT initiation. Risk of HF was decreased in the antagonist group compared with the GnRH agonist group among patients with prior CVD (hazard ratio [HR], 0.46; 95% CI, 0.26-0.79). Risk of IHD was decreased in the antagonist group in patients without prior CVD (HR, 0.26; 95% CI, 0.11-0.65). Use of antagonist was associated with an increased risk of arrhythmia among patients with no prior CVD (HR, 2.34; 95% CI, 1.63-3.36). CONCLUSIONS: Compared with GnRH agonists, the GnRH antagonist was found to be associated with a decreased risk of HF, specifically among patients with prior CVD. Among those with no prior CVD, the GnRH antagonist was associated with a decreased risk of IHD but an increased risk of arrhythmia.

Association of pediatric cardiac surgery-associated acute kidney injury with post-discharge healthcare utilization, mortality and kidney outcomes.

BACKGROUND: Acute kidney Injury (AKI) in children undergoing cardiac surgery (CS) is strongly associated with hospital morbidity. Post-discharge CS AKI outcomes are less clear. We evaluated associations between AKI and post-discharge (a) healthcare utilization, (b) chronic kidney disease (CKD) or hypertension and (c) mortality. METHODS: This is a retrospective two-centre cohort study of children surviving to hospital discharge after CS. Primary exposures were post-operative ≥Stage 1 AKI and ≥Stage 2 AKI defined by Kidney Disease Impoving Global Outcomes. Association of AKI with time to outcomes was determined using multivariable Cox-Proportional Hazards analysis. RESULTS: Of 350 participants included (age 3.1 (4.5) years), 180 [51.4%] developed AKI and 60 [17.1%] developed ≥Stage 2 AKI. Twenty-eight (9%) participants developed CKD or hypertension (composite outcome), and 17 (5%) died within 5 years of discharge. Post-operative ≥Stage 1 and ≥Stage 2 AKI were not associated with post-discharge hospitalizations, emergency room (ER) visits, physician visits or CKD or hypertension in adjusted analyses. A trend was observed between ≥Stage 2 AKI and mortality but was not statistically significant. In unadjusted stratified analyses, AKI was associated with post-discharge hospitalizations in children with RACHS-1 score ≥3, complex chronic disease classification and children living in urban areas. CONCLUSIONS: Post-CS AKI is not associated with post-discharge healthcare utilization, death and CKD or hypertension, though it may be associated with healthcare utilization in more complex paediatric CS children. Studies should aim to better understand post-CS healthcare utilization patterns and non-AKI risk factors for CKD, hypertension and mortality, to reduce adverse long-term outcomes after CS.

Acute kidney injury in critically ill children and 5-year hypertension.

BACKGROUND: To develop a pediatric-specific hypertension algorithm using administrative data and use it to evaluate the association between acute kidney injury (AKI) in the intensive care unit (ICU) and hypertension diagnosis 5 years post-discharge. METHODS: Two-center retrospective cohort study of children (≤ 18 years old) admitted to the pediatric ICU in Montreal, Canada, between 2003 and 2005 and followed until 2010. Patients with a valid healthcare number and without end-stage renal disease were included. Patients who could not be merged with the provincial database, did not survive admission, underwent cardiac surgery, had pre-existing renal disease associated with hypertension or a prior diagnosis of hypertension were excluded. AKI defined using the Kidney Disease: Improving Global Outcomes (KDIGO) definition. Using diagnostic codes and medications from administrative data, novel pediatric-specific hypertension definitions were designed. Both the evaluation of the prevalence of hypertension diagnosis and the association between AKI and hypertension occurred. RESULTS: Nineteen hundred and seventy eight patients were included (median age at admission [interquartile range] 4.3 years [1.1-11.8], 44% female, 325 (16.4%) developed AKI). Of these patients, 130 (7%) had a hypertension diagnosis 5 years after discharge. Patients with AKI had a higher prevalence of hypertension diagnosis [non-AKI: 84/1653 (5.1%) vs. AKI: 46/325 (14.2%), p < .001]. Children with AKI had a higher adjusted risk of hypertension diagnosis (hazard ratio [95% confidence interval] 2.19 [1.47-3.26]). CONCLUSIONS: Children admitted to the ICU have a high prevalence of hypertension post-discharge and children with AKI have over two times higher risk of hypertension compared to those with no AKI.

Impact of the introduction of novel hormonal agents on metastatic castration-resistant prostate cancer treatment choice.

BACKGROUND: Docetaxel-based chemotherapy has been the cornerstone of the management of symptomatic metastatic castration-resistant prostate cancer (mCRPC) since 2004. This study aimed to describe how real-world clinical practice was changed with the public funding of novel hormonal agents (abiraterone and enzalutamide) in Quebec. METHODS: We conducted a retrospective cohort study in two McGill University hospitals. Hospital-based cancer registries were used to select mCRPC patients in medical oncology departments from January 2010 to June 2014. Two groups according to mCRPC diagnosis year were built, with 2012 chosen as the cut-off year, corresponding to the year abiraterone was approved for public reimbursement in second-line in Quebec. Kaplan-Meier analysis was used to estimate time to first docetaxel prescription since mCRPC diagnosis before and after 2012. Cox regression was used to identify predictive factors of docetaxel and novel hormonal agent use. RESULTS: In our cohort, 308 patients diagnosed with mCRPC were selected with 162 patients in the pre-2012 group and 146 patients in the post-2012 group. The median age at mCRPC was 74.0 years old. At 12 months from diagnosis, 69% of patients received a prescription for docetaxel in the pre-2012 group comparatively to 53% in the post-2012 group. Factors that decreased the likelihood of docetaxel utilization were: age older than 80 at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3-0.7), mCRPC diagnosis after 2012 (HR: 0.6; 95%CI: 0.4-0.8), and asymptomatic disease at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3-0.7). CONCLUSION: The introduction of novel hormonal agents reduced first-line and overall docetaxel utilization and delayed time to its initiation.

Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort.

Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2.68 × 10-5, P = 5.81 × 10-4, and P = 5.94 × 10-4, respectively). Required doses of warfarin were the highest for homozygotes of the minor allele at the VDR variants (P < 0.0026). Variants in the VDR gene were associated with the variability in response to warfarin, emphasizing the possible clinical relevance of nuclear receptor gene variants on the inter-individual variability in drug metabolism.

Lasso Regression for the Prediction of Intermediate Outcomes Related to Cardiovascular Disease Prevention Using the TRANSIT Quality Indicators.

BACKGROUND: Cardiovascular disease morbidity and mortality are largely influenced by poor control of hypertension, dyslipidemia, and diabetes. Process indicators are essential to monitor the effectiveness of quality improvement strategies. However, process indicators should be validated by demonstrating their ability to predict desirable outcomes. The objective of this study is to identify an effective method for building prediction models and to assess the predictive validity of the TRANSIT indicators. METHODS: On the basis of blood pressure readings and laboratory test results at baseline, the TRANSIT study population was divided into 3 overlapping subpopulations: uncontrolled hypertension, uncontrolled dyslipidemia, and uncontrolled diabetes. A classic statistical method, a sparse machine learning technique, and a hybrid method combining both were used to build prediction models for whether a patient reached therapeutic targets for hypertension, dyslipidemia, and diabetes. The final models' performance for predicting these intermediate outcomes was established using cross-validated area under the curves (cvAUC). RESULTS: At baseline, 320, 247, and 303 patients were uncontrolled for hypertension, dyslipidemia, and diabetes, respectively. Among the 3 techniques used to predict reaching therapeutic targets, the hybrid method had a better discriminative capacity (cvAUCs=0.73 for hypertension, 0.64 for dyslipidemia, and 0.79 for diabetes) and succeeded in identifying indicators with a better capacity for predicting intermediate outcomes related to cardiovascular disease prevention. CONCLUSIONS: Even though this study was conducted in a complex population of patients, a set of 5 process indicators were found to have good predictive validity based on the hybrid method.

Is there a potential association between spironolactone and the risk of new-onset diabetes in a cohort of older patients with heart failure?

PURPOSE: Some evidence suggests that spironolactone may have a deleterious effect on glucose homeostasis. The objective of this study was to assess whether spironolactone use is associated with a higher risk of developing diabetes in a large cohort of patients with heart failure (HF). METHODS: Two Quebec government administrative databases were used to identify a cohort of hospitalized patients discharged between January 1995 and December 2009 with a primary discharge diagnosis of HF and without secondary discharge diagnosis of diabetes. Patients were categorized as new users of spironolactone and non-users. The primary outcome was defined as new-onset diabetes (NOD) during 5 years of follow-up and was ascertained using ICD codes for diabetes or use of hypoglycemic agents. RESULTS: Among the 2974 patients that were included in the cohort analysis, 769 were given a new prescription of spironolactone. The incidence rate of NOD was similar among spironolactone users (5.0 per 100 person-years) and non-users (4.9 per 100 person-years). There was no significant association between the use of spironolactone and NOD in the crude, unadjusted model (hazard ratio (HR) 1.01; 95% confidence interval (CI) 0.80-1.28; p = 0.9217), and it remained unchanged in the adjusted Cox proportional hazard model (HR = 0.92; 95% CI = 0.72-1.18; p = 0.5227). The results were consistent with those observed in sensitivity analyses of a 1:3 propensity score-matched cohort (HR = 0.97; CI = 0.76-1.25; p = 0.8169). CONCLUSION: We found no evidence supporting the claim that use of spironolactone is associated with a higher risk of diabetes among patients hospitalized for HF.

Concordance of care processes between medical records and patient self-administered questionnaires.

BACKGROUND: Despite the increasing use of medical records to measure quality of care, studies have shown that their validity is suboptimal. The objective of this study is to assess the concordance of cardiovascular care processes evaluated through medical record review and patient self-administered questionnaires (SAQs) using ten quality indicators (TRANSIT indicators). These indicators were developed as part of a participatory research program (TRANSIT study) dedicated to TRANSforming InTerprofessional clinical practices to improve cardiovascular disease (CVD) prevention in primary care. METHODS: For every patient participating in the TRANSIT study, the compliance to each indicator (individual scores) as well as the mean compliance to all indicators of a category (subscale scores) and to the complete set of ten indicators (overall scale score) were established. Concordance between results obtained using medical records and patient SAQs was assessed by prevalence-adjusted bias-adjusted kappa (PABAK) coefficients as well as intraclass correlation coefficients (ICCs) and 95% confidence intervals (95% CI). Generalized linear mixed models (GLMM) were used to identify patients' sociodemographic and clinical characteristics associated with agreement between the two data sources. RESULTS: The TRANSIT study was conducted in a primary care setting among patients (n = 759) with multimorbidity, at moderate (16%) and high risk (83%) of cardiovascular diseases. Quality of care, as measured by the TRANSIT indicators, varied substantially between medical records and patient SAQ. Concordance between the two data sources, as measured by ICCs (95% CI), was poor for the subscale (0.18 [0.08-0.27] to 0.46 [0.40-0.52]) and overall (0.46 [0.40-0.53]) compliance scale scores. GLMM showed that agreement was not affected by patients' characteristics. CONCLUSIONS: In quality improvement strategies, researchers must acknowledge that care processes may not be consistently recorded in medical records. They must also be aware that the evaluation of the quality of care may vary depending on the source of information, the clinician responsible of documenting the interventions, and the domain of care.

Association Between Metformin Adherence and All-Cause Mortality Among New Users of Metformin: A Nested Case-Control Study.

BACKGROUND: Metformin presents better survival rates than other oral antidiabetics in the treatment of type 2 diabetes. However, these benefits may be dampened by inadequate treatment adherence. OBJECTIVE: We aimed to investigate the relationship between adherence level to metformin therapy and all-cause mortality over 10 years in incident metformin users. METHODS: A nested case-control study was conducted using a large cohort of beneficiaries of the Quebec public drug insurance plan, aged 45 to 85 years, who initiated metformin between 2000 and 2009. Each case of all-cause death during follow-up was matched with up to 10 controls. Adherence to metformin was measured using the medication possession ratio (MPR). Conditional logistic regression models were used to estimate rate ratios (RRs) for mortality between adherent (MPR ≥ 80%) and nonadherent patients (MPR < 80%). Subgroup analyses were conducted according to age (45-64 and 65-85 years) and comedication use (antihypertensive/cardiovascular drugs and statins). RESULTS: The cohort included 82 720 incident metformin users, followed up for 2.4 [0.8-4.4] years (median [interquartile range]) and 4747 cases of all-cause deaths. Analyses revealed decreased mortality risks after long-term adherence to metformin. Specifically, RRs were 0.84 (95% CI = [0.71-0.98]) and 0.69 [0.57-0.85] after 4 to 6 and ≥6 years of adherence to metformin, respectively. Survival benefits of long-term adherence (≥4 years) were also observed across most subgroups and particularly in patients using neither antihypertensive/cardiovascular drugs nor statins (0.57 [0.41-0.77]). CONCLUSIONS: Long-term adherence to metformin is associated with decreased risks of all-cause mortality in incident metformin users. Further research should investigate whether survival benefits vary according to the comorbidity burden of patients.

Older adults with heart failure treated with carvedilol, bisoprolol, or metoprolol tartrate: risk of mortality.

PURPOSE: The long-term use of ß-blockers has been shown to improve clinical outcomes among patients with heart failure (HF). However, a lack of data persists in assessing whether carvedilol or bisoprolol are superior to metoprolol tartrate in clinical practice. We endeavored to compare the effectiveness of ß-blockers among older adults following a primary hospital admission for HF. METHODS: We conducted a cohort study using Quebec administrative databases to identify patients who were using ß-blockers, carvedilol, bisoprolol, or metoprolol tartrate after the diagnosis of HF. We characterized the patients by the type of ß-blocker prescribed at discharge of their first HF hospitalization. An adjusted multivariate Cox proportional hazards model was used to compare the primary outcome of all-cause mortality. We also conducted analyses by matching for a propensity score for initiation of ß-blocker therapy and assessed the effect on primary outcome. RESULTS: Among 3197 patients with HF with a median follow-up of 2.8 years, the crude annual mortality rates (per 100 person-years) were at 16, 14.9, and 17.7 for metoprolol tartrate, carvedilol, and bisoprolol, respectively. Adjusted hazard ratios of carvedilol (hazard ratio 0.92; 0.78-1.09) and bisoprolol (hazard ratio 1.04; 0.93-1.16) were not significantly different from that of metoprolol tartrate in improving survival. After matching for propensity score, carvedilol and bisoprolol showed no additional benefit with respect to all-cause mortality compared with metoprolol tartrate. CONCLUSIONS: Our evidence suggests no differential effect of ß-blockers on all-cause mortality among older adults with HF. Copyright © 2016 John Wiley & Sons, Ltd.

Predictors of Direct Oral Anticoagulants Utilization for Thromboembolism Prevention in Atrial Fibrillation.

PURPOSE: Several factors have been associated with the prescription of direct oral anticoagulants (DOAC) over warfarin such as younger age, fewer concomitant medications, and lower CHADS2 or bleeding scores. The primary objective of this study was to identify predictors of DOAC choice compared with warfarin for patients who are starting a new oral anticoagulant (OAC) for atrial fibrillation (AF). The secondary objective was to describe the proportion of DOAC prescriptions in new users of OAC for AF. METHODS: A retrospective cross-sectional study was conducted in a teaching hospital in Canada. Medical records of adult patients hospitalized in any medical units between October 1st, 2011 and October 1st, 2014, who were newly prescribed an OAC for non valvular AF were systematically reviewed. Baseline characteristics of warfarin and DOAC users were compared and a multivariate logistic regression analysis was completed to identify predictors of DOAC use. Variables included in the multiple regression analysis were: age, hypertension, diabetes, history of stroke or transient ischemic attack, coronary artery disease, peripheral arterial disease, CHADS2 score of 2 or more, creatinine clearance 30mL/min or more, polypharmacy, concomitant use of ASA or clopidogrel, and prescription by a neurologist. RESULTS: Among OAC users (144 patients on DOAC and 295 patients on warfarin), older age (odds ratio [OR] 0.97; 95%CI 0.95-0.98), peripheral arterial disease (OR: O.41;95%CI: 0.21-0.82), polypharmacy (OR: 0.30;95%CI:0.10-0.89), and concomitant use of clopidogrel (OR: 0.19;95%CI:0.07-0.56) decreased the probability of DOAC use. Prescription by a neurologist (OR: 2.77;95%CI:1.34-5.76) and an estimated creatinine clearance of at least 30mL/min (OR: 3.53;95%CI:1.18-10.57) increased the likelihood of DOAC prescription. CONCLUSION: To the best of our knowledge, this is the first observational study finding that concomitant use of clopidogrel reduced the likelihood of DOAC utilization while prescription by a neurologist increased the probability of receiving a DOAC over warfarin in patients with AF.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Psychometric analysis of the TRANSIT quality indicators for cardiovascular disease prevention in primary care.

OBJECTIVE: To assess a selection of psychometric properties of the TRANSIT indicators. DESIGN: Using medical records, indicators were documented retrospectively during the 14 months preceding the end of the TRANSIT study. SETTING: Primary care in Quebec, Canada. PARTICIPANTS: Indicators were documented in a random subsample (n = 123 patients) of the TRANSIT study population (n = 759). INTERVENTIONS: For every patient, the mean compliance to all indicators of a category (subscale score) and to the complete set of indicators (overall scale score) were established. To evaluate test-retest and inter-rater reliabilities, indicators were applied twice, two months apart, by the same evaluator and independently by different evaluators, respectively. To evaluate convergent validity, correlations between TRANSIT indicators, Burge et al. indicators and Institut national d'excellence en santé et en services sociaux (INESSS) indicators were examined. MAIN OUTCOME MEASURES: Test-retest reliability, inter-rater reliability, and convergent validity. RESULTS: Test-retest reliability, as measured by intraclass correlation coefficients (ICCs) was equal to 0.99 (0.99-0.99) for the overall scale score while inter-rater reliability was equal to 0.95 (0.93-0.97) for the overall scale score. Convergent validity, as measured by Pearson's correlation coefficients, was equal to 0.77 (P < 0.001) for the overall scale score when the TRANSIT indicators were compared to Burge et al. indicators and to 0.82 (P < 0.001) for the overall scale score when the TRANSIT indicators were compared to INESSS indicators. CONCLUSIONS: Reliability was excellent except for eleven indicators while convergent validity was strong except for domains related to the management of CVD risk factors.

Whole-genome sequencing in French Canadians from Quebec.

Genome-wide association studies (GWAS) have had a tremendous success in the identification of common DNA sequence variants associated with complex human diseases and traits. However, because of their design, GWAS are largely inappropriate to characterize the role of rare and low-frequency DNA variants on human phenotypic variation. Rarer genetic variation is geographically more restricted, supporting the need for local whole-genome sequencing (WGS) efforts to study these variants in specific populations. Here, we present the first large-scale low-pass WGS of the French-Canadian population. Specifically, we sequenced at ~5.6× coverage the whole genome of 1970 French Canadians recruited by the Montreal Heart Institute Biobank and identified 29 million bi-allelic variants (31 % novel), including 19 million variants with a minor allele frequency (MAF) <0.5 %. Genotypes from the WGS data are highly concordant with genotypes obtained by exome array on the same individuals (99.8 %), even when restricting this analysis to rare variants (MAF <0.5, 99.9 %) or heterozygous sites (98.9 %). To further validate our data set, we showed that we can effectively use it to replicate several genetic associations with myocardial infarction risk and blood lipid levels. Furthermore, we analyze the utility of our WGS data set to generate a French-Canadian-specific imputation reference panel and to infer population structure in the Province of Quebec. Our results illustrate the value of low-pass WGS to study the genetics of human diseases in the founder French-Canadian population.

Impact of regular physical activity on weekly warfarin dose requirement.

Warfarin is an oral anticoagulant agent with a narrow therapeutic index. There is a marked inter- and intra-patient variability in warfarin dose requirement. All factors influencing warfarin response are not known and this study aims to evaluate if regular physical activity (RPA) is a determining factor. RPA level was collected with the Stanford Brief Activity Survey in 1064 incident warfarin users, as part of the Quebec Warfarin Cohort (QWC), and with the Global Physical Activity Questionnaire in 618 patients from the Montreal Heart Institute (MHI) Biobank. Linear regression was performed to model relationship of warfarin dose after 3 months of therapy in the QWC with RPA, while controlling for height, weight, age, CYP2C9 (*2 and *3 alleles) and VKORC1 (*2 allele) genotype. Warfarin dose of prevalent users was modeled in the MHI Biobank for replication. A higher level of physical activity was associated with higher doses of warfarin in both cohorts. In the QWC, physical activity could explain 5.4 % (P < 0.001) and 0.9 % (P = 3.23 × 10(-5)) of variance in dose, in univariate and multivariable models, respectively. Similarly, RPA was found to be associated with 1.7 % (P = 0.0012) and 0.5 % (P = 0.0391) of inter-individual variability in warfarin dose requirement before and after adjustment for other covariables, respectively. RPA is associated with higher warfarin dose requirement. The relevance of clinical recommendations on RPA to maintain a steady response to warfarin should be assessed in further studies.

Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth weight: a systematic review and meta-analysis of randomized and quasi-randomized trials.

BACKGROUND: It is known that antimalarial drugs reduce the risk of low birth weight (LBW) in pregnant patients. However, a previous Cochrane review did not evaluate whether the level of antimalarial drug resistance could modify the protective effect of antimalarial drugs in this regard. In addition, no systematic review exists comparing current recommendations for malaria prevention during pregnancy to alternative regimens in Africa. Therefore, we conducted a comprehensive systematic review and meta-analysis to assess the efficacy of antimalarial drugs for malaria prevention during pregnancy in reducing the risk of LBW. METHODS: We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for articles published up to 21 November 2014, in English or French, and identified additional studies from reference lists. We included randomized and quasi-randomized studies reporting LBW as one of the outcomes. We extracted data and assessed the risk of bias in selected studies. All pooled analyses were based on a random effect model, and we used a funnel plot and trim and fill method to test and adjust for publication bias. RESULTS: A total of 25 studies met the inclusion criteria (37,981 subjects). Compared to no use, all combined antimalarial drugs were associated with a 27% (RR 0.73, 95% CI 0.56-0.97, ten studies) reduction in the risk of LBW. The level of antimalarial drug resistance modified the protective effect of the antimalarial drug used for prevention of LBW during pregnancy. Sulfadoxine-pyrimethamine was not associated with a reduction in the risk of LBW in regions where the prevalence of the dihydropteroate synthase 540E mutation exceeds 50% (RR 0.99, 95% CI 0.80-1.22, three studies). The risk of LBW was similar when sulfadoxine-pyrimethamine was compared to mefloquine (RR 1.05, 95% CI 0.86-1.29, two studies). CONCLUSION: Prophylactic antimalarial drugs and specifically sulfadoxine-pyrimethamine may no longer protect against the risk of LBW in areas of high-level resistance. In Africa, there are currently no suitable alternative drugs to replace sulfadoxine-pyrimethamine for malaria prevention during pregnancy.

Validation of patient-reported warfarin dose in a prospective incident cohort study.

PURPOSE: Inconsistencies in the definition and the collection of warfarin dosing data could lead to bias in observational, clinical, and pharmacogenetic studies. The present study aims to assess the concordance between patient-reported and prescribed warfarin doses among new warfarin users in the Quebec Warfarin Cohort (QWC) study. METHODS: Demographic, clinical, and lifestyle data were collected at cohort entry and each three months during a 1-year follow-up period among a subgroup of 219 patients from the prospective QWC study. We evaluated the differences between reported and prescribed warfarin doses overall and at each follow-up period. Concordance was tested in a multivariate generalized linear mixed model and allowed to vary from 95% to 105% of the prescribed dose. RESULTS: Overall, there was no significant difference between reported and prescribed warfarin doses (p>0.05, Pearson coefficient=0.969, power=100%). There was also no significant difference across each of four timepoints tested (p>0.05). We found that 84.0% of the reported warfarin doses were concordant with the prescribed doses. Having a history of myocardial infarction was significantly associated with a low concordance (OR=0.494; CI 95%: 0.286-0.852). CONCLUSION: In our population, we found that patient-reported warfarin dose and prescribed warfarin dose were comparable for the conduct of observational and clinical studies as well as for the validation and implementation of warfarin dosing algorithms. Moreover, the effect was similar whether measured in new-onset users of warfarin and after up to 12 months of use.

Antipsychotics and Risks of Cardiovascular and Cerebrovascular Diseases and Mortality in Dwelling Community Older Adults.

This study aims to investigate the effect of antipsychotic agents on cardiovascular and cerebrovascular diseases (CVD/CEV) and mortality risks in the older population living in a community. A cohort of 42,650 new users of antipsychotic agents was built using Quebec healthcare databases (1998-2011). The outcomes were CVD/CEV and mortality incidence in 5 years of follow-up in the total cohort, sub-cohort of patients with no schizophrenia/dementia, sub-cohort with schizophrenia, and sub-cohort with dementia. Comparisons were made between the new users who continued the treatment (adherent level ≥ 60%) vs. those ceasing treatment (adherence level < 60%) using inverse probability of treatment weighting and Cox models. Comparing high adherence vs. low levels, CVD/CEV risk was increased by 36% in the sub-cohort with schizophrenia for atypical antipsychotic users and by 25% in the sub-cohort with dementia for typical antipsychotic users. An increasing mortality risk of 2- to 3-fold was linked with the typical antipsychotic use in all cohorts except the sub-cohort with schizophrenia; in addition, mortality risk is linked with the use of high vs. low doses. Antipsychotics were not linked with CVD/CEV risk, except for atypical antipsychotics in patients with schizophrenia and typical antipsychotics in patients with dementia. The mortality risk was linked with the use of typical antipsychotics and the dose used.