Rejane Dillenburg

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how

BackgroundSensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.DiscussionIn this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.SummaryWhen reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

A systematic scoping review of adherence to reporting guidelines in health care literature

Background Reporting guidelines have been available for the past 17 years since the inception of the Consolidated Standards of Reporting Trials statement in 1996. These guidelines were developed to improve the quality of reporting of studies in medical literature. Despite the widespread availability of these guidelines, the quality of reporting of medical literature remained suboptimal. In this study, we assess the current adherence practice to reporting guidelines; determine key factors associated with better adherence to these guidelines; and provide recommendations to enhance adherence to reporting guidelines for future studies. Methods We undertook a systematic scoping review of systematic reviews of adherence to reporting guidelines across different clinical areas and study designs. We searched four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Web of Science, Embase, and Medline) from January 1996 to September 2012. Studies were included if they addressed adherence to one of the following guidelines: Consolidated Standards of Reporting Trials (CONSORT), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Quality of Reporting of Meta-analysis (QUOROM), Transparent Reporting of Evaluations with Nonrandomized Designs (TREND), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). A protocol for this study was devised. A literature search, data extraction, and quality assessment were performed independently by two authors in duplicate. This study reporting follows the PRISMA guidelines. Results Our search retrieved 5159 titles, of which 50 were eligible. Overall, 86.0% of studies reported suboptimal levels of adherence to reporting guidelines. Factors associated with better adherence included journal impact factor and endorsement of guidelines, publication date, funding source, multisite studies, pharmacological interventions and larger studies. Conclusion Reporting guidelines in the clinical literature are important to improve the standards of reporting of clinical studies; however, adherence to these guidelines remains suboptimal. Action is therefore needed to enhance the adherence to these standards. Strategies to enhance adherence include journal editorial policies endorsing these guidelines.

Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE study): a cohort study protocol examining the mechanisms of obesity in survivors of childhood brain tumours

Background Childhood obesity has reached epidemic proportions and is impacting childrens health globally. In adults, obesity is associated with chronic low-grade inflammation that leads to insulin resistance, which is one of the important mechanisms through which dysregulation of metabolism occurs. There is limited information available about the contribution of inflammation to metabolic health in obese children, and how individual and lifestyle factors impact this risk. One of the paediatric groups at risk of higher rates of obesity includes the survivors of childhood brain tumours. The aim of this study was to evaluate the mechanisms that contribute to inflammation in obese survivors of childhood brain tumours. Methods and analysis This is a prospective cohort study. We will recruit lean and obese survivors of childhood brain tumours, and a control group composed of lean and obese children with no history of tumours. We will measure circulating and urinary cytokine levels and cytokine gene expression in monocytes. In addition, the methylation patterns of cytokine genes and that of toll-like receptor genes will be evaluated. These will be correlated with individual and lifestyle factors including age, sex, ethnicity, puberty, body mass index, fasting lipid levels, insulin sensitivity, diet, exercise, sleep, stress and built environment. The sample size calculation showed that we need 25 participants per arm Ethics and dissemination This study has received ethics approval from the institutional review board. Once completed, we will publish this work in peer-reviewed journals and share the findings in presentations and posters in meetings. Discussion This study will permit the interrogation of inflammation as a contributor to obesity and its complications in obese survivors of childhood brain tumours and compare them with lean survivors and lean and obese controls with no history of tumours, which may help identify therapeutic and preventative interventions to combat the rising tide of obesity.

To tilt or not to tilt: what is the question?

Syncope in children and adolescents is common, with 15 % estimated to have had at least one syncopal episode by age 18 [15, 16]. The most frequent cause of fainting in this age group is vasovagal syncope [7, 15, 16]. Although the clinical presentation of vasovagal syncope is frequently typical and the disorder is benign, further testing is sometimes necessary to confirm the diagnosis. Not infrequently, children with recurrent syncope are incorrectly diagnosed as having epilepsy. The introduction of head-up tilt testing (HUT), by Kenny and Sutton in 1986, as a diagnostic procedure in patients with unexplained syncope, improved our ability to diagnose vasovagal syncope [10]. Unfortunately, there is still no general consensus regarding the best HUT protocol and studies using different protocols report a wide range of diagnostic accuracy and specificity [4]. Few studies have assessed the usefulness of HUT in the pediatric population.

Recruitment feasibility to a cohort study of endocrine and metabolic health among survivors of childhood brain tumours: a report from the Canadian study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE)

Objectives The aim of this study was to test the feasibility of recruitment and performance of study procedures of the Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE) study, which was designed to assess the determinants of endocrine and metabolic health in survivors of childhood brain tumours. Setting A single paediatric tertiary care centre in Hamilton, Ontario, Canada. Participants We included boys and girls, aged 5 years and older, who were lean (body mass index (BMI) below 85th centile for age and gender) or overweight/obese (BMI 85th centile or above for age and gender). We excluded children on steroids or immunosuppressant therapy, smokers and those who had an active infection for the 2 weeks prior to participation. Outcomes Feasibility targets included recruitment rate of at least 50%, the consenting of 80% of participants to provide biological samples, 90% questionnaire completion rate and the ability to process biological samples from at least 80% of participants. Results We approached 210 potential participants, and of the 112 (53%) who agreed to participate, 30 (26.8%) completed the study visit over 7 months. All participants agreed to fast, provide biological samples and complete the questionnaires. Sample collection was successful in 97% (29/30) of participants and laboratory procedures were feasible in 100% of collected samples. We also tested resources required for the conduct of the full study including personnel, space, laboratory equipment and procedures and determined that they are all feasible. Conclusions Recruitment and consenting of patients for the CanDECIDE study may be feasible. However, we are considering prolonging recruitment duration and collaboration with other centres to meet recruitment targets due to lower than expected recruitment rate. Completion of questionnaires and implementation of sample processing protocols are feasible.

Age-Related Head-Up-Tilt Test Cardiac-Hemodynamic Profile in Vasovagal Syncope

Objective To determine the age-related cardio-hemodynamic profile (CHP) during head up tilt test (HUT) in patients with neurally mediated syncope (NMS). Methods 97 subjects (M/F=43/54) with a clinical history of NMS and normal structural heart underwent HUT (70°) 30-minute protocol. 73 patients had positive HUT response (mean time to syncope of 19±7 min) and were included for study analysis. Patients were divided in three study groups for comparison according to age: A = 66 years old (77±6). Beat-to-Beat heart rate (HR, bpm), mean blood pressure (MAP) and cardiac impedance were recorded and total peripheral resistance index (TPRI, dyne*s*m2/cm^5) and left ventricular work index (LVWI, mmHg*l/min/m2) were calculated using the Task Force Monitor (CNSystem, AU). Variables were compared at rest, 5 minutes of HUT (ES) and during -2 and -5 minutes prior to the onset of syncope. One-way ANOVA and Students t test were applied. Results Variables are shown as means ± SD. Increased baseline HR was found in younger patients (Group A) compared with group B and C (76±15 vs. 67±12, p=0.017; 76±15 vs. 69±11, p=0.076). No statistical differences were found in MAP during HUT comparing groups. TPRI and LVWI are shown in the table as follows ![Graphic][1] Conclusion Distinct age-related CHP alterations can be documented in patients with NMS provoked by HUT. Younger NMS patients have an increased chronotropic and inotropic activity during rest and OS as well as a decreased vascular reactivity during HUT. Central and peripheral cardiovascular compensatory mechanisms during orthostatic stress may trigger distinct vasovagal responses that vary depending on age. [1]: /embed/graphic-1.gif

3. Vasovagal Syncope, Tilt Testing

Objective To determine the age-related cardio-hemodynamic profile (CHP) during head up tilt test (HUT) in patients with neurally mediated syncope (NMS). Methods 97 subjects (M/F=43/54) with a clinical history of NMS and normal structural heart underwent HUT (70°) 30-minute protocol. 73 patients had positive HUT response (mean time to syncope of 19±7 min) and were included for study analysis. Patients were divided in three study groups for comparison according to age: A = 66 years old (77±6). Beat-to-Beat heart rate (HR, bpm), mean blood pressure (MAP) and cardiac impedance were recorded and total peripheral resistance index (TPRI, dyne*s*m2/cm^5) and left ventricular work index (LVWI, mmHg*l/min/m2) were calculated using the Task Force Monitor (CNSystem, AU). Variables were compared at rest, 5 minutes of HUT (ES) and during -2 and -5 minutes prior to the onset of syncope. One-way ANOVA and Students t test were applied. Results Variables are shown as means ± SD. Increased baseline HR was found in younger patients (Group A) compared with group B and C (76±15 vs. 67±12, p=0.017; 76±15 vs. 69±11, p=0.076). No statistical differences were found in MAP during HUT comparing groups. TPRI and LVWI are shown in the table as follows ![Graphic][1] Conclusion Distinct age-related CHP alterations can be documented in patients with NMS provoked by HUT. Younger NMS patients have an increased chronotropic and inotropic activity during rest and OS as well as a decreased vascular reactivity during HUT. Central and peripheral cardiovascular compensatory mechanisms during orthostatic stress may trigger distinct vasovagal responses that vary depending on age. [1]: /embed/graphic-1.gif