Equity and Game-Theory Strategies to Promote Gender Diversity and Inclusion in an Academic Health Science Centre.

BACKGROUND: Achieving diversity, inclusion, and gender equity remains an elusive challenge for many institutions worldwide and is understudied in Canadian academic health science centres. METHODS: McMaster University's Department of Medicine undertook surveys and analyses to determine whether there was inequity in leadership positions and salaries, or unprofessional behaviour within the department. Measures of academic productivity in relation to gender for both educators and researchers were analyzed. The department began shifting policies to foster greater gender diversity and inclusion. A revision of the leadership selection process, incorporating tenets of equity and a new game theory-based strategy called Diversitive Agreement Versus Nash Equilibrium (DAvNE) was evaluated. RESULTS: The department's survey revealed underrepresentation of women and people of colour in leadership positions, with perceived barriers to their promotion. Both women and people of colour reported experiencing unprofessional behaviour directed toward them. A gender gap in base salary was observed, with female full professors being paid less. No difference in academic productivity was seen between male and female educators or researchers. The leadership competitions conducted under new selection processes emphasizing diversity resulted in 66% of participating women securing a leadership position, in comparison to 25% of participating men. People of colour made up 27% of members participating in these leadership competitions, but none was successful in obtaining a position. CONCLUSIONS: Diversity and inclusion disparities in the Department of Medicine at McMaster University indicate a need for further efforts and innovation to bring about greater gender and racial equity.

CONTEXTE: La mise en place des conditions nécessaires à la diversité, à l'inclusion et à l'équité des genres demeure un défi difficile à relever pour de nombreux établissements dans le monde entier. C'est une démarche peu étudiée dans les centres universitaires canadiens des sciences de la santé. MÉTHODOLOGIE: Le département de médecine de l'Université McMaster a mené des sondages et des analyses en vue de déterminer s'il existait en son sein même des iniquités en matière d'attribution des postes de direction et de fixation des salaires, ou des comportements non professionnels. Des mesures de la productivité universitaire des éducateurs et des chercheurs ont été analysées en fonction des genres. Le département a entrepris une réforme de ses politiques afin de favoriser une plus grande diversité et inclusion des genres. Une révision du processus de sélection des candidats aux postes de direction, intégrant les principes d'équité et une nouvelle stratégie fondée sur la théorie des jeux appelée Diversitive Agreement Versus Nash Equilibrium (DAvNE [accord de diversité vs équilibre de Nash]), a été évaluée. RÉSULTATS: Le sondage du département a révélé qu'il existait une sous-représentation des femmes et des personnes de couleur parmi les titulaires des postes de direction, ainsi que des obstacles perçus à leur promotion. Tant les femmes que les personnes de couleur ont fait état de comportements non professionnels à leur endroit. Un écart entre les genres a été observé au chapitre de la rémunération de base, les professeurs titulaires de sexe féminin étant moins rémunérées. Aucune différence n'a été observée sur le plan de la productivité universitaire entre les femmes et les hommes au sein de l'effectif des éducateurs et des chercheurs. Les concours pour les postes de direction ont été organisés en fonction de nouveaux processus de sélection mettant l'accent sur la diversité. Au final, 66 % des candidats qui ont vu leur candidature retenue étaient des femmes et 25 %, des hommes. Dans le cadre de ces concours, 27 % des candidats étaient des personnes de couleur, mais aucun n'a réussi à obtenir un poste. CONCLUSIONS: Les disparités notées en matière de diversité et d'inclusion au sein du département de médecine de l'Université McMaster montrent que l'atteinte d'une plus grande équité des genres et des races passe par des efforts et une innovation soutenus.

GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA). STUDY DESIGN AND SETTING: We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically. RESULTS: Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies. CONCLUSION: Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias, and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. STUDY DESIGN AND SETTING: We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. RESULTS: Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. CONCLUSION: Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. Although several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

Test-retest properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire and its constituent domains.

BACKGROUND: The Patient Reported Outcomes, Burdens and Experiences (PROBE) study aims to develop and validate questionnaire for assessing health status in patients with haemophilia and participants without bleeding disorders. OBJECTIVE: To investigate the test-retest properties of the PROBE questionnaire. METHODS: The PROBE questionnaire covers four domains and is comprised of 29 questions. People with haemophilia (PWH) and participants without bleeding disorder were invited to participate in this study. All participants were asked to complete the PROBE questionnaire three times (paper-based survey on two consecutive days: T1 and T2 and then a web-based version: T3). Test-retest properties and percentage agreement were analysed. RESULTS: A total of 63 participants were enrolled in this study with a median age of 50 (range: 17-76) years. Of these, 30 (47.6%) were PWH. On the questions common to PWH and participants without bleeding disorder, Kappa coefficients ranged from 0.69 to 1.00, indicating substantial to almost perfect agreement (T1 vs T2). For haemophilia-related questions (T1 vs T2), Kappa coefficients ranged from 0.5 to 1.0. Of these, 5 of 11 items were in perfect agreement (Kappa = 1.0). The web-based questionnaire (T3) showed substantial to almost perfect agreement with the paper version (T1 test-retest properties were comparable between PWH and individuals without a bleeding disorder). CONCLUSIONS: The results suggest that PROBE is a reliable tool to assess patient-reported outcomes for PWH and benchmark data in participants without bleeding disorder. The web-based questionnaire and the standard paper-based version can be used interchangeably.

Andexanet alfa for the treatment of hemorrhage.

INTRODUCTION: While associated life-threatening and fatal bleeding events are less frequent with the direct factor Xa inhibitors compared to vitamin K antagonists, significant concern surrounding management of major bleeds and urgent periprocedural interruption of these agents exists among clinicians. Andexanet alfa is a recombinant human factor Xa decoy protein developed in response to this clinical gap in the care of patients receiving anticoagulation with factor Xa inhibitors. Areas covered: This paper reviews results from preclinical and healthy-volunteer studies demonstrating the ability of andexanet to rapidly and reliably normalize coagulation indices in patients treated with both direct and indirect factor Xa inhibitors. An interim analysis from an ongoing phase 3/4b clinical study assessing the efficacy and safety of andexanet in patients experiencing life-threatening hemorrhage in association with factor Xa inhibitors is discussed. It also provides an overview of the major safety concerns reported in these trials which include allergic and infusion reactions, development of anti-andexanet antibodies and, importantly, thrombosis. Expert commentary: While initial reports on restoration of hemostasis and safety are promising, further study of andexanet is required to gauge its efficacy and toxicity, including a potential prothrombotic effect. Further, its use in patients requiring urgent surgery should be studied.

Psychometric properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire.

OBJECTIVE: To assess the psychometric properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire. METHODS: This study was a cross-sectional, multinational study. Participants were enrolled if they were more than 10 years old and people with haemophilia A or B or people without a bleeding disorder. Participants were invited through non-governmental patient organisations in 21 countries between 01/27/2016 and 02/23/2017. The following psychometric properties: missing data, floor and ceiling effects, exploratory factor analysis and internal consistency reliability were examined. A PROBE Score was derived and assessed for its convergent and known groups validity. RESULTS: The study analysed the data on 916 participants with median age of 37.0 (IQR 27.0 to 48.0) years, 74.8% male. In the domain assessing patient-reported outcomes (PROs), more than 15% of participants presented a ceiling effect for all items but two, and a floor effect for one item. Factor analysis identified three factors explaining the majority of the variance. Cronbach's alpha coefficient indicated good internal consistency reliability (0.84). PROBE items showed moderate to strong correlations with corresponding EuroQol five dimension 5-level instrument (EQ-5D-5L) domains. The PROBE Score has a strong correlation (r=0.67) with EQ-5D-5L utility index score. The PROBE Score has a known groups validity among various groups. CONCLUSIONS: The results of this study suggest that PROBE is a valid questionnaire for evaluating PROs in people with haemophilia as well as control population. The known-group property of PROBE will allow its use in future clinical trials, longitudinal studies, health technology assessment studies, routine clinical care or registries. Additional studies are needed to test responsiveness and sensitivity to change. TRIAL REGISTRATION NUMBER: NCT02439710; Results.

Assessment of the Measurement Error in Cyclosporine Levels Drawn Between Peripheral and Central Sources.

OBJECTIVES: Cyclosporine is often monitored by drug levels drawn through central venous catheters (CVCs), which may be falsely elevated due to reversible drug adsorption onto the catheter. Therefore, we assessed the correlation between cyclosporine levels drawn peripherally and through CVCs. METHODS: Bone marrow transplantation patients had a weekly collection of both peripheral and CVC draws from dual-lumen catheters simultaneously to assess cyclosporine levels after research ethics approval. Our primary outcome was the proportion of paired samples that were incongruent-defined as the mean of the CVC level being greater than 2 standard deviations from the peripheral level mean. RESULTS: After approaching 27 eligible patients, 20 patients (77.8%) provided samples. Of 53 paired samples, seven were incongruent (13.2%). Peripheral and CVC levels correlated (r = 0.91) and agreed well. CONCLUSION: Despite potential for preanalytical error due to adsorption, cyclosporine infusion and monitoring via CVCs produce results similar to monitoring via peripheral blood draws.

Dalteparin versus vitamin K antagonists for the prevention of recurrent venous thromboembolism in patients with cancer and renal impairment: a Canadian pharmacoeconomic analysis.

BACKGROUND: Patients with cancer are at increased risk of venous thromboembolism (VTE) and the risk is further elevated after a primary VTE. To reduce the risk of recurrent events, extended prophylaxis with vitamin K antagonists (VKA) is available for use. However, in a large randomized trial (Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer [CLOT]; Lee et al), extended duration dalteparin reduced the relative risk of recurrent VTE by 52% compared to VKA (p=0.002). A recent subgroup analysis of patients with moderate-to-severe renal impairment also revealed lower absolute VTE rates with dalteparin (3% vs. 17%; p=0.011). To measure the economic value of dalteparin as an alternative to VKA, a patient-level cost utility analysis was conducted from a Canadian perspective. METHODS: Resource use data captured during the CLOT trial were extracted and linked to 2015 Canadian unit cost estimates. Health state utilities were then measured using the Time-Trade-Off technique in 24 randomly selected members of the general Canadian public to estimate the gains in quality-adjusted life years (QALYs). RESULTS: For the entire CLOT trial population (n=676), the dalteparin group had significantly higher mean costs compared to the VKA group ($Can5,771 vs. $Can2,569; p<0.001). However, the utility assessment revealed that 21 of 24 respondents (88%) selected dalteparin over VKA, with an associated gain of 0.14 (95% confidence interval [CI]: 0.10-0.18) QALYs. When the incremental cost of dalteparin was combined with the QALY gain, dalteparin had a cost of $Can23,100 (95% CI: $Can19,200-$Can25,800) per QALY gained. The analysis in patients with renal impairment suggested even better economic value with the cost per QALY gained being <$14,000. CONCLUSION: Extended duration dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer, especially in those with renal impairment.

Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review.

BACKGROUND: Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban. METHODS: PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results. RESULTS: We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r2 = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r2 = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban. CONCLUSIONS: An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available.

Examining the clinical use of hemochromatosis genetic testing.

BACKGROUND: Hereditary hemochromatosis leads to an increased lifetime risk for end-organ damage due to excess iron deposition. Guidelines recommend that genetic testing be performed in patients with clinical suspicion of iron overload accompanied by elevated serum ferritin and transferrin saturation levels. OBJECTIVE: To evaluate guideline adherence and the clinical and economic impact of HFE genetic testing. METHODS: The electronic charts of patients submitted for HFE testing in 2012 were reviewed for genetic testing results, biochemical markers of iron overload and clinical history of phlebotomy. RESULTS: A total of 664 samples were sent for testing, with clinical, biochemical and phlebotomy data available for 160 patients. A positive C282Y homozygote or C282Y/H63D compound heterozygote test result was observed in 18% of patients. Patients with an at-risk HFE genotype had significantly higher iron saturation, serum iron and hemoglobin (P<0.001), without higher ferritin or liver enzyme levels. Fifty percent of patients referred for testing did not have biochemical evidence of iron overload (transferrin saturation >45% and ferritin level >300 µg/L). Patients were four times more likely to undergo phlebotomy if they were gene test positive (RR 4.29 [95% CI 2.35 to 7.83]; P<0.00001). DISCUSSION: One-half of patients referred for testing did not exhibit biochemical evidence of iron overload. Many patients with biochemical evidence of iron overload, but with negative genetic test results, did not undergo phlebotomy. A requisition to determine clinical indication for testing may reduce the use of the HFE genetic test. Finally, improvement of current genetic test characteristics would improve rationale for the test. CONCLUSION: A significant proportion of hemochromatosis genetic testing does not adhere to current guidelines and would not alter patient management.

Challenges in Measuring Benefit of Clinical Research Training Programs--the ASH Clinical Research Training Institute Example.

The American Society of Hematology developed the Clinical Research Training Institute (CRTI) to address the lack of training in patient-oriented research among hematologists. As the program continues, we need to consider metrics for measuring the benefits of such a training program. This article addresses the benefits of clinical research training programs. The fundamental and key components are education and mentorship. However, there are several other benefits including promotion of collaboration, job and advancement opportunities, and promotion of work-life balance. The benefits of clinical research training programs need to be measured so that funders and society can judge if they are worth the investment in time and resources. Identification of elements that are important to program benefit is essential to measuring the benefit of the program as well as program planning. Future work should focus on the constructs which contribute to benefits of clinical research training programs such as CRTI.

Brand name versus generic warfarin: a systematic review of the literature.

The use of generic drugs has become increasingly common in clinical practice. However, for drugs with a narrow therapeutic index, such as warfarin, there may be some concern regarding the definition of bioequivalence. Clinical studies that compared brand name and generic warfarin products provided conflicting results. Therefore, we performed a systematic review of the literature to better assess the characteristics of each generic warfarin product. Several sources were searched, including MEDLINE and EMBASE, electronic records of meetings' abstracts, and reference lists of included articles. Articles were considered relevant if they were original studies, enrolled patients receiving oral anticoagulant treatment, and compared any approved generic warfarin with brand name warfarin in at least one clinical, laboratory, or management outcome. Eleven studies, with a total of more than 40,000 patients, were included; five were randomized controlled trials, and six were observational studies. In three crossover trials evaluating the mean difference of the international normalized ratio (INR) after switching to the alternate formulation of warfarin, no statistically significant difference was found between patients randomly assigned to receive brand name or generic warfarin. The two other randomized trials found no significant differences in the magnitude or number of dosage changes between patients switched to brand name or generic warfarin. The results of the observational studies are more conflicting, suggesting different features for different generic warfarin products. In these observational studies, the time in the therapeutic range and the number of thromboembolic and hemorrhagic complications were similar in studies that compared the anticoagulation control before and after the switch to a generic warfarin product. In one observational study, however, a change in therapeutic INR control after the switch to generic warfarin was reported at the individual patient level. The results of our systematic review suggest that generic warfarin products may be as safe and effective as brand name products and that patients may be safely treated with these products. However, closer monitoring may be reasonable when switching brands, as variations in individual INR response may be seen.

The vexing problem of guidelines and conflict of interest: a potential solution.

Issues of financial and intellectual conflict of interest in clinical practice guidelines have raised increasing concern. Professional organizations have responded by more rigorous regulation of conflict of interest. Nevertheless, tension remains between the competing goals of optimizing guideline quality by using the experience and insight of experts and ensuring that financial and intellectual conflicts of interest do not influence recommendations. The executive committee of the American College of Chest Physicians' Antithrombotic Guidelines has developed a strategy comprising 3 innovative aspects to address this tension: First, place equal emphasis on intellectual and financial conflicts and provide explicit criteria for both; second, a methodologist without important conflicts of interest should have primary responsibility for each chapter; and third, experts with important financial or intellectual conflicts of interest can collect and interpret evidence, but only panel members without important conflicts can be involved in developing the recommendation for a specific question. These strategies may help to achieve the benefits of expert input without conflicts of interest influencing recommendations.

2009 evidence-based clinical practice guidelines for diagnosing a first episode of lower extremities deep vein thrombosis in ambulatory outpatients.

INTRODUCTION: The GRADE working group has recently suggested a rigorous framework for clinical practice guidelines (CPG) addressing diagnostic tests and test strategies based on the impact of alternative approaches on patient-important outcomes. The framework mandates explicit evidence summaries, ratings of the quality of evidence, and specifying recommendations as strong or weak. OBJECTIVES: To test the feasibility and performance of the GRADE approach, we applied this framework to well-researched issues in the diagnoses of deep venous thrombosis (DVT). METHODS: A 16-member panel with interest in thromboembolism and CPG development identified pertinent clinical questions. Our search for relevant studies included existing CPG and systematic reviews. We summarized the data in form of evidence tables and developed recommendations including, when needed, a formal consensus process. RESULTS AND CONCLUSIONS: We provide three groups of recommendations for clinicians practicing in settings with access to different types of D-dimer tests -- highly sensitive, moderately sensitive, and no availability of D-dimer. We consider the use of clinical prediction rules in guiding the diagnostic process, the potential for negative D-dimer or venous ultrasound (US) to rule out disease, and the role of follow-up testing (US following positive D-dimer result, D-dimer following negative US, and serial US) depending on the probability of DVT at the start of diagnostic process. We recommend the following: that clinicians without access to a highly or moderately sensitive D-dimer test rely on US to guide DVT diagnosis; that those with access use the highly sensitive D-dimer to determine, in patients with low or moderate probability of DVT (by the Wells rule) whether US is needed; that in patients with low pre-test probability (pre-TP) and a negative D-dimer (either highly or moderately sensitive) they follow patients without further testing; that in patients with high pre-test probability they perform a compression ultrasound without D-dimer testing.

Evidence-based guidelines--an introduction.

Recommendations in the form of clinical practice guidelines are increasingly common. Clinical guidelines are systematically developed statements designed to help administrators, practitioners and patients make decisions about appropriate health care for specific circumstances. In North America, guidelines developed by professional societies, government panels and cooperative groups are frequently used to measure quality, to allocate resources and to determine how health care dollars are spent. For clinicians, guidelines provide a summary of the relevant medical literature and offer assistance in deciding which diagnostic tests to order, which treatments to use for specific conditions, when to discharge patients from the hospital, and many other aspects of clinical practice.

Human-derived D-dimer for external quality assessment: results of four surveys in Ontario.

External quality assessment (EQA) of D-dimer assays has been limited by a lack of standardized human-derived testing material. In 2006 and 2007, the Quality Management Program--Laboratory Services, Toronto, Canada, investigated the use of commercially prepared lyophilized human plasma spiked with human-derived D-dimer components manufactured by Affinity Biologicals, Hamilton, Canada. Four surveys were performed. Participants reported the level or presence of D-dimer using quantitative or qualitative methods. Participants performing quantitative testing provided their unit of measure and reference interval. Results were considered correct if they fell within the range appropriate for each sample (normal/negative or abnormal/positive). Overall, survey results were excellent, with 4.0% (95% confidence interval [CI], 1.3%-9.1%), 0.8% (CI, 0.0%-1.5%), 2.3% (CI, 0.5%-6.6%), and 2.3% (CI, 0.4%-6.6%) of participants reporting an incorrect result in the first, second, third, and fourth surveys, respectively. A commercially prepared D-dimer is a suitable material for EQA testing.