A systematic, concept-based method of developing the exposure measure for drug safety and effectiveness studies.

PURPOSE: In drug safety and effectiveness studies based on secondary data, the choice of an appropriate exposure measure for a given outcome can be challenging. Different measures of exposure can yield different estimates of treatment effect and safety. There is a knowledge gap with respect to developing and refining measures of drug exposure, to ensure that the exposure measure addresses the study question and is suitable for statistical analysis. METHODS: We present a transparent, step-by-step approach to the development of drug exposure measures involving secondary data. This approach would be of interest to students and investigators with initial training in pharmacoepidemiology. We illustrate the approach using a study about Parkinson's disease. RESULTS: We described the exposure specifications according to the study question. Next, we refined the exposure measure by linking it to knowledge about four major concepts in drug safety and effectiveness studies: drug use patterns, duration, timing, and dose. We then used this knowledge to guide the ultimate choice of exposure measure: time-varying, cumulative 6-month exposure to tamsulosin (a drug used to treat prostate hyperplasia). CONCLUSIONS: The proposed approach links exposure specifications to four major concepts in drug safety and effectiveness studies. Formulating subject-matter knowledge about these major concepts provides an avenue to develop the rationale and specifications for the exposure measure.

Variation in surgical demand and time to hip fracture repair: a Canadian database study.

BACKGROUND: Competing demands for operative resources may affect time to hip fracture surgery. We sought to determine the time to hip fracture surgery by variation in demand in Canadian hospitals. METHODS: We obtained discharge abstracts of 151,952 patients aged 65 years or older who underwent surgery for a hip fracture between January, 2004 and December, 2012 in nine Canadian provinces. We compared median time to surgery (in days) when demand could be met within a two-day benchmark and when demand required more days, i.e. clearance time, to provide surgery, overall and stratified by presence of medical reasons for delay. RESULTS: For persons admitted when demand corresponded to a 2-day clearance time, 68% of patients underwent surgery within the 2-day benchmark. When demand corresponded to a clearance time of one week, 51% of patients underwent surgery within 2 days. Compared to demand that could be served within the two-day benchmark, adjusted median time to surgery was 5.1% (95% confidence interval [CI] 4.1-6.1), 12.2% (95% CI 10.3-14.2), and 22.0% (95% CI 17.7-26.2) longer, when demand required 4, 6, and 7 or more days to clear the backlog, respectively. After adjustment, delays in median time to surgery were similar for those with and without medical reasons for delay. CONCLUSION: Increases in demand for operative resources were associated with dose-response increases in the time needed for half of hip fracture patients to undergo surgery. Such delays may be mitigated through better anticipation of day-to-day supply and demand and increased response capability.

Mortality effects of timing alternatives for hip fracture surgery.

BACKGROUND: The appropriate timing of hip fracture surgery remains a matter of debate. We sought to estimate the effect of changes in timing policy and the proportion of deaths attributable to surgical delay. METHODS: We obtained discharge abstracts from the Canadian Institute for Health Information for hip fracture surgery in Canada (excluding Quebec) between 2004 and 2012. We estimated the expected population-average risks of inpatient death within 30 days if patients were surgically treated on day of admission, inpatient day 2, day 3 or after day 3. We weighted observations with the inverse propensity score of surgical timing according to confounders selected from a causal diagram. RESULTS: Of 139 119 medically stable patients with hip fracture who were aged 65 years or older, 32 120 (23.1%) underwent surgery on admission day, 60 505 (43.5%) on inpatient day 2, 29 236 (21.0%) on day 3 and 17 258 (12.4%) after day 3. Cumulative 30-day in-hospital mortality was 4.9% among patients who were surgically treated on admission day, increasing to 6.9% for surgery done after day 3. We projected an additional 10.9 (95% confidence interval [CI] 6.8 to 15.1) deaths per 1000 surgeries if all surgeries were done after inpatient day 3 instead of admission day. The attributable proportion of deaths for delays beyond inpatient day 2 was 16.5% (95% CI 12.0% to 21.0%). INTERPRETATION: Surgery on admission day or the following day was estimated to reduce postoperative mortality among medically stable patients with hip fracture. Hospitals should expedite operating room access for patients whose surgery has already been delayed for nonmedical reasons.

The burden of second hip fractures: provincial surgical hospitalizations over 15 years.

BACKGROUND: Second hip fractures account for up to 15% of all hip fractures. We sought to determine if the proportion of hip fracture surgeries for second hip fracture changed over time in terms of patient and fracture characteristics. METHODS: We reviewed the records of patients older than 60 years hospitalized for hip fracture surgery between 1990 and 2005 in British Columbia. We studied the proportion of surgeries for second hip fracture among all hip fracture surgeries. Linear regression tested for trends across fiscal years for women and men. RESULTS: We obtained 46 341 patient records. Second hip fracture accounted for 8.3% of hip fracture surgeries. For women the proportion of second hip fracture surgeries increased linearly from 4% to 13% with each age decade (p = 0.001) and across fiscal years (p = 0.002). In men the proportion of second hip fracture surgeries was 5% for each age decade between the ages of 60 and 90 years across fiscal years, increasing to 8% for men older than 90 years across fiscal years (p = 0.20). These sex-specific trends were similar for both pertrochanteric and transcervical fracture types. CONCLUSION: Second hip fracture surgeries account for an increasing proportion of hip fracture surgeries and may require more health care resources to minimize poorer reported outcomes. Future research should determine whether more health care resources are required to manage these patients and optimize their outcomes.

CONTEXTE: Les secondes fractures de la hanche représentent jusqu'à 15 % de la totalité des fractures de la hanche. Nous avons tenté de déterminer si la proportion de chirurgies de seconde fracture de la hanche avait évolué au fil du temps sur le plan des caractéristiques des patients et des fractures. MÉTHODES: Nous avons examiné les dossiers des patients de 60 ans et plus qui avaient été hospitalisés pour une chirurgie de fracture de la hanche entre 1990 et 2005, en Colombie-Britannique. De ce total, nous avons ensuite déterminé le nombre de chirurgies de seconde fracture de la hanche. L'analyse de régression linéaire a déterminé les tendances au cours des années financières pour les femmes et les hommes. RÉSULTATS: Nous avons obtenu 46 341 dossiers de patient. Les secondes fractures de la hanche représentaient 8,3 % de la totalité des chirurgies de fracture de la hanche. Chez les femmes, la proportion de seconde fracture de la hanche augmentait de façon linéaire de 4 % à 13 % pour chaque tranche d'âge de 10 ans (p = 0,001) et sur l'ensemble des années financières (p = 0,002). Chez les hommes, la proportion de chirurgies de seconde fracture de la hanche était de 5 % pour chaque tranche d'âge de 10 ans entre 60 et 90 ans et sur l'ensemble des années financières, et augmentait à 8 % pour les hommes de plus de 90 ans sur l'ensemble des années financières (p = 0,20). Ces tendances selon le sexe étaient similaires tant pour les fractures pertrochantériennes que pour les fractures transcervicales. CONCLUSION: Les chirurgies de seconde fracture de la hanche représentent une proportion croissante de la totalité des chirurgies de fracture de la hanche et pourraient nécessiter davantage de ressources en soins de santé pour minimiser les résultats moins bons signalés. Les recherches futures devraient déterminer s'il faut davantage de ressources de soins de santé pour la prise en charge de ces patients et l'optimisation de leurs résultats.

In-hospital mortality after hip fracture by treatment setting.

BACKGROUND: Where patients with hip fracture undergo treatment may influence their outcome. We compared the risk of in-hospital death after hip fracture by treatment setting in Canada. METHODS: We examined all discharge abstracts from the Canadian Institute for Health Information with diagnosis codes for hip fracture involving patients 65 years and older who were admitted to hospital with a nonpathological first hip fracture between Jan. 1, 2004, and Dec. 31, 2012, in Canada (excluding Quebec). We compared the risk of in-hospital death, overall and after surgery, between teaching hospitals and community hospitals of various bed capacities, accounting for variation in length of stay. RESULTS: Compared with the number of deaths per 1000 admissions at teaching hospitals, there were an additional 3 (95% confidence interval [CI] 1-6), 14 (95% CI 10-18) and 43 (95% CI 35-51) deaths per 1000 admissions at large, medium and small community hospitals, respectively. For the risk of in-hospital death overall, the adjusted odds ratios (ORs) were 1.05 (95% CI 0.99-1.11), 1.16 (95% CI 1.09-1.24) and 1.44 (95% CI 1.31-1.57) at large, medium and small community hospitals, respectively, compared with teaching hospitals. For the risk of postsurgical death in hospital, the adjusted ORs were 1.06 (95% CI 1.00-1.13), 1.13 (95% CI 1.04-1.23) and 1.18 (95% CI 0.87-1.60) at large, medium and small community hospitals, respectively. INTERPRETATION: Compared with teaching hospitals, the risk of in-hospital death among patients with hip fracture was higher at medium and small community hospitals, and the risk of in-hospital death after surgery was higher at medium community hospitals. No differences were found between teaching and large community hospitals. Future research should examine the role of volume, demand and bed occupancy for observed differences.

The effect of treatment timing on repeat revascularization in patients with stable ischemic heart disease.

Objectives: In patients with stable ischemic heart disease, there is no evidence for the effect of revascularization treatment timing on the need for repeat procedures. We aimed to determine if repeat revascularizations differed among patients who received coronary artery bypass graft surgery after the time recommended by physicians compared with those who had timely percutaneous coronary intervention. Methods: We identified 25,520 British Columbia residents 60 years or older who underwent first-time nonemergency revascularization for angiographically proven, stable left main or multivessel ischemic heart disease between January 1, 2001, and December 31, 2016. We estimated unadjusted and adjusted cumulative incidence functions for repeat revascularization, in the presence of death as a competing risk, after index revascularization or last staged percutaneous coronary intervention for patients undergoing delayed coronary artery bypass grafting compared with timely percutaneous coronary intervention. Results: After adjustment with inverse probability of treatment weights, at 3 years, patients who underwent delayed coronary artery bypass grafting had a statistically significant lower cumulative incidence of a repeat revascularization compared with patients who received timely percutaneous coronary intervention (4.84% delayed coronary artery bypass grafting, 12.32% timely percutaneous coronary intervention; subdistribution hazard ratio, 0.16, 95% CI, 0.04-0.65). Conclusions: Patients who undergo delayed coronary artery bypass grafting have a lower cumulative incidence of repeat revascularization than patients who undergo timely percutaneous coronary intervention. Patients who want to wait to receive coronary artery bypass grafting will see the benefit of lower repeat revascularization over percutaneous coronary intervention unaffected by a delay in treatment.

Evaluating adverse drug event reporting in administrative data from emergency departments: a validation study.

BACKGROUND: Adverse drug events are a frequent cause of emergency department presentations. Administrative data could be used to identify patients presenting with adverse drug events for post-market surveillance, and to conduct research in patient safety and in drug safety and effectiveness. However, such data sources have not been evaluated for their completeness with regard to adverse drug event reporting. Our objective was to determine the proportion of adverse drug events to outpatient medications diagnosed at the point-of-care in emergency departments that were documented in administrative data. METHODS: We linked the records of patients enrolled in a prospective observational cohort study on adverse drug events conducted in two Canadian tertiary care emergency departments to their administrative data. We compared the number of adverse drug events diagnosed and recorded at the point-of-care in the prospective study with the number of adverse drug events recorded in the administrative data. RESULTS: Among 1574 emergency department visits, 221 were identified as adverse drug event-related in the prospective database. We found 15 adverse drug events documented in administrative records with ICD-10 codes clearly indicating an adverse drug event, indicating a sensitivity of 6.8% (95% CI 4.0-11.2%) of this code set. When the ICD-10 code categories were broadened to include codes indicating a very likely, likely or possible adverse event to a medication, 62 of 221 events were identifiable in administrative data, corresponding to a sensitivity of 28.1% (95% CI 22.3-34.6%). CONCLUSIONS: Adverse drug events to outpatient medications were underreported in emergency department administrative data compared to the number of adverse drug events diagnosed and recorded at the point-of-care.

Sex differences in heart disease prevalence among individuals with spinal cord injury: A population-based study.

CONTEXT/OBJECTIVE: The risk for cardiovascular disease is amplified following spinal cord injury, but whether risk differs between the sexes remains unknown. Here, we evaluated sex differences in the prevalence of heart disease among individuals with spinal cord injury, and compared sex differences with able-bodied individuals. DESIGN: The design was a cross-sectional study. Multivariable logistic regression analysis was conducted, using inverse probability weighting to account for the sampling method and to adjust for confounders. SETTING: Canada. PARTICIPANTS: Individuals who participated in the national Canadian Community Health Survey. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Self-reported heart disease. RESULTS: Among 354 individuals with spinal cord injury, the weighted prevalence of self-reported heart disease was 22.9% in males and 8.7% in females, with an inverse-probability weighted odds ratio of 3.44 (95% CI 1.70-6.95) for males versus females. Among 60,605 able-bodied individuals, the prevalence of self-reported heart disease was 5.8% in males and 4.0% in females, with an inverse probability weighted odds ratio of 1.62 (95% CI 1.50-1.75) for males versus females. The effect of male sex on increasing heart disease prevalence was about two times higher among individuals with spinal cord injury than able-bodied individuals (relative difference in inverse probability weighted odds ratios = 2.12, 95% CI 1.08-4.51). CONCLUSION: Males with spinal cord injury exhibit a significantly higher prevalence of heart disease, compared with females with spinal cord injury. Moreover, relative to able-bodied individuals, spinal cord injury amplifies sex-related differences in heart disease. Overall, this work will inform targeted cardiovascular prevention strategies, and may also inform a better understanding of cardiovascular disease progression in both able-bodied and individuals with spinal cord injury.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease.

OBJECTIVE: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). METHODS: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [¹¹C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [¹¹C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[¹8F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. RESULTS: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. INTERPRETATION: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms.

An observational study to evaluate 2 target times for elective coronary bypass surgery.

BACKGROUND: Guidelines for timing of elective bypass surgery were established by expert opinion; yet, there is little evidence to support the recommended target times. OBJECTIVES: To estimate the effect of timing of the procedure on in-hospital mortality by comparing groups of patients that differ in the duration of time between decision to operate and performed procedure. RESEARCH DESIGN: We used a population-based registry to identify patients who underwent surgical coronary revascularization and their hospital discharge summaries to identify in-hospital death. SUBJECTS: We studied 9593 patients who underwent surgical revascularization between 1992 and 2006 after registration on a wait list for first-time isolated coronary artery bypass grafting on an elective basis. MEASURES: The outcome was postoperative in-hospital death. The study variable was the timing of surgery, categorized as short, prolonged, and excessive delays according to the guidelines. METHODS: The probability of in-hospital death in relation to timing of surgery was modeled by logistic regression that included a precalculated risk score for in-hospital death, with weighting observations by inverse propensity scores for the 3 surgery timing groups. RESULTS: In-hospital death among patients with short delays was one third as likely as among those with excessive delays: adjusted odds ratio=0.32 (95% confidence interval 0.20-0.51). The protective effect was smaller and not significant for patients with prolonged delays; odds ratio=0.78 (95% confidence interval, 0.38-1.63). CONCLUSIONS: Our findings suggest a survival benefit from performing elective surgical revascularization within the time frame recommended by the stricter of the 2 guidelines. Our results have implications for health systems that provide universal coverage and that budget the annual number of procedures.

Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease.

Parkinson's disease is a relentlessly progressive neurodegenerative disease. Breakdown of compensatory mechanisms influencing putaminal dopamine processing could contribute to the progressive motor symptoms. We studied a cohort of 78 subjects (at baseline) with sporadic Parkinson's disease and 35 healthy controls with multi-tracer positron emission tomography scans to investigate the evolution of adaptive mechanisms influencing striatal dopamine processing in Parkinson's disease progression. Presynaptic dopaminergic integrity was assessed with three radioligands: (i) [(11)C](±)dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [(11)C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[(18)F]fluoro-L-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[(18)F]-fluorodopamine in synaptic vesicles. The subjects with Parkinson's disease and the healthy controls underwent positron emission tomography scans at the initial visit and after 4 and 8 years of follow-up. Non-linear multivariate regression analyses with random effects were utilized to model the longitudinal changes in tracer values in the putamen standardized relative to normal controls. We found evidence for possible upregulation of dopamine synthesis and downregulation of dopamine transporter in the more severely affected putamen in the early stage of Parkinson's disease. The standardized 6-[(18)F]fluoro-L-DOPA and [(11)C]d-threo-methylphenidate values tended to approach [(11)C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [(11)C](±)dihydrotetrabenazine values <25% of normal), when the rates of decline in the positron emission tomography measurements were similar for all the markers. Our data suggest that compensatory mechanisms decline as Parkinson's disease progresses. This breakdown of compensatory strategies in the putamen could contribute to the progression of motor symptoms in advanced disease.

Effectiveness of educational interventions on asthma self-management in Punjabi and Chinese asthma patients: a randomized controlled trial.

BACKGROUND: Asthma tends to be less well controlled among ethnic minority groups, and its prevalence in new immigrants increases significantly the longer they are in Canada; mainly due to their lack of familiarity with English and difficulty understanding information regarding the disease, health literacy, cultural issues, housing conditions, and lack of access to appropriate care services. OBJECTIVE: To explore the effectiveness of different formats of culturally relevant information and its impact on asthma patients' self-management within the Punjabi, Mandarin, and Cantonese communities. METHODS: Using a participatory approach, we developed and tested knowledge and community educational videos (with similar information, but used a different approach, i.e., scientific vs. colloquial) and a pictorial pamphlet. A total of 92 physician-diagnosed adult asthma patients (47 Chinese and 45 Punjabi) were assigned at random to three experimental groups (watched one or both videos) and one comparison group (read pictorial pamphlet) and participated in three in-person interviews and one telephone interview within a 9-month period. Patients received education on asthma self-management via videos and pamphlet and outcomes, including their knowledge of asthma triggers (environmental-related and behavioral-related triggers) and symptoms; inhaler use skills and patient-reported medication adherence were measured. RESULTS: Knowledge of asthma symptoms, inhaler use, and understanding of physician's instructions improved significantly from pretest to 3 months post-intervention follow-up among all participants. CONCLUSIONS: Participants performed significantly better at follow-up than they did at baseline assessment, with the most notable improvements observed in the group that watched both community and knowledge videos. The results suggest that short, simple, culturally, and linguistically appropriate interventions can promote knowledge gain about asthma and improve inhaler use that can be sustained over the short term. Such interventions that provide authentic learning materials that draw on patients' life experiences and sociocultural context can overcome certain limitations of conventional patient education approaches.

Evaluation of supply-side initiatives to improve access to coronary bypass surgery.

BACKGROUND: Guided by the evidence that delaying coronary revascularization may lead to symptom worsening and poorer clinical outcomes, expansion in cardiac surgery capacity has been recommended in Canada. Provincial governments started providing one-time and recurring increases in budgets for additional open heart surgeries to reduce waiting times. We sought to determine whether the year of decision to proceed with non-emergency coronary bypass surgery had an effect on time to surgery. METHODS: Using records from a population-based registry, we studied times between decision to operate and the procedure itself. We estimated changes in the length of time that patients had to wait for non-emergency operation over 14 calendar periods that included several years when supplementary funding was available. We studied waiting times separately for patients who access surgery through a wait list and through direct admission. RESULTS: During two periods when supplementary funding was available, 1998-1999 and 2004-2005, the weekly rate of undergoing surgery from a wait list was, respectively, 50% and 90% higher than in 1996-1997, the period with the longest waiting times. We also observed a reduction in the difference between 90th and 50th percentiles of the waiting-time distributions. Forty percent of patients in the 1998, 1999, 2004 and 2005 cohorts (years when supplementary funding was provided) underwent surgery within 16 to 20 weeks following the median waiting time, while it took between 27 and 37 weeks for the cohorts registered in the years when supplementary funding was not available. Times between decision and surgery were shorter for direct admissions than for wait-listed patients. Among patients who were directly admitted to hospital, time between decision and surgery was longest in 1992-1993 and then has been steadily decreasing through the late nineties. The rate of surgery among these patients was the highest in 1998-1999, and has not changed afterwards, even for years when supplementary funding was provided. CONCLUSIONS: Waiting times for non-emergency coronary bypass surgery shortened after supplementary funding was granted to increase volume of cardiac surgical care in a health system with publicly-funded universal coverage for the procedure. The effect of the supplementary funding was not uniform for patients that access the services through wait lists and through direct admission.

Time of coronary revascularization: methodology of a mediation analysis study.

BACKGROUND: The advantage of coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI), established in trials, may not be generalizable to populations in which the method of treatment determines the time to treatment. We sought to describe the methodology of a population-based observational study for assessing how changes in time to treatment may affect the comparative effectiveness of these 2 methods of coronary revascularization. METHODS: We propose a framework of causal mediation analysis to compare the outcomes of choosing CABG over PCI, if patients selected for either method waited the same amount of time had they undergone a PCI. We will include patients who underwent a first-time, nonurgent isolated CABG or single-session PCI for multivessel or left main coronary artery disease from January 2001 to December 2016, in British Columbia. We will use absolute risk difference as a measure of the total effect of choosing CABG over PCI and partition it into the direct effect of the treatment choice and the effect mediated by the treatment-specific timing. INTERPRETATION: Understanding how time to treatment mediates the relation between method of revascularization and outcomes will have implications for treatment selection, resource allocation and planning benchmarks. Findings on the benefits and risks of performing PCI or CABG within a certain time will guide multidisciplinary teams in determining the appropriate revascularization method for individual patients.

Outcomes of emergency department patients presenting with adverse drug events.

STUDY OBJECTIVE: Our objectives are to describe the outcomes of patients presenting to the emergency department (ED) because of an adverse drug event and to compare them with outcomes of patients presenting for other reasons. METHODS: This prospective observational study was conducted at Vancouver General Hospital, a 955-bed tertiary care hospital. We prospectively enrolled adults presenting to the ED between March and June 2006, using a systematic sampling algorithm. Pharmacists and physicians independently evaluated patients for adverse drug events. An independent committee reviewed and adjudicated cases in which assessments were discordant or uncertain. Data from the index visit were linked to vital statistics, administrative health services utilization, and cost of care data. RESULTS: Of 1,000 patients, 122 (12.2%; 95% confidence interval [CI] 10.3% to 14.4%) presented to the ED because of an adverse drug event. Of these, 48 presented because of an adverse drug reaction (one type of adverse drug event defined as an unintended response that occurred despite use of an appropriate drug dosage). We found no difference in mortality among patients presenting with and without adverse drug reactions (14.6% versus 5.9%; hazard ratio 1.57; 95% CI 0.70 to 3.52). After adjustment, patients with adverse drug events had a higher risk of spending additional days in the hospital per month (6.3% versus 3.4%; odds ratio 1.52; 95% CI 1.43 to 1.62) and higher rate of outpatient health care encounters (1.73 versus 1.22; rate ratio 1.20; 95% CI 1.03 to 1.40). The adjusted median monthly cost of care was 1.90 times higher (Can $325 versus $96; 95% CI 1.18 to 3.08). CONCLUSION: ED patients presenting with an adverse drug event incurred greater health services utilization and costs during a 6-month follow-up period compared with patients presenting for other reasons.

Constructing treatment episodes from concomitant medication logs: a prospective observational study.

OBJECTIVES: To describe an approach using concomitant medication log records for the construction of treatment episodes. Concomitant medication log records are routinely collected in clinical studies. Unlike prescription and dispensing records, concomitant medication logs collect utilisation data. Logs can provide information about drug safety and drug repurposing. DESIGN: A prospective multicentre, multicohort observational study. SETTING: Twenty-one clinical sites in the USA, Europe, Israel and Australia. PARTICIPANTS: 415 subjects from the de novo cohort of the Parkinson's Progression Markers Initiative. METHODS: We construct treatment episodes of concomitant medication use. The proposed approach treats temporal gaps as a stoppage of medication and temporal overlaps as simultaneous use or changes in dose. Log records with no temporal gaps were combined into a single treatment episode. RESULTS: 5723 concomitant medication log records were used to construct 3655 treatment episodes for 65 medications. There were 405 temporal gaps representing a stoppage of medication; 985 temporal overlaps representing simultaneous regimens of the same medication and 2696 temporal overlaps representing a change in dose regimen. The median episode duration was 37 months (IQ interval: 11-73 months). CONCLUSIONS: The proposed approach for constructing treatment episodes offers a method of estimating duration and dose of treatment from concomitant medication log records. The accompanying recommendations guide log data collection to improve their quality for drug safety and drug repurposing.

Effect of school-based physical activity interventions on body mass index in children: a meta-analysis.

BACKGROUND: The prevalence of childhood obesity is increasing at an alarming rate. Many local governments have enacted policies to increase physical activity in schools as a way to combat childhood obesity. We conducted a systematic review and meta-analysis to determine the effect of school-based physical activity interventions on body mass index (BMI) in children. METHODS: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials up to September 2008. We also hand-searched relevant journals and article reference lists. We included randomized controlled trials and controlled clinical trials that had objective data for BMI from before and after the intervention, that involved school-based physical activity interventions and that lasted for a minimum of 6 months. RESULTS: Of 398 potentially relevant articles that we identified, 18 studies involving 18 141 children met the inclusion criteria. The participants were primarily elementary school children. The study duration ranged from 6 months to 3 years. In 15 of these 18 studies, there was some type of co-intervention. Meta-analysis showed that BMI did not improve with physical activity interventions (weighted mean difference -0.05 kg/m(2), 95% confidence interval -0.19 to 0.10). We found no consistent changes in other measures of body composition. INTERPRETATION: School-based physical activity interventions did not improve BMI, although they had other beneficial health effects. Current population-based policies that mandate increased physical activity in schools are unlikely to have a significant effect on the increasing prevalence of childhood obesity.

On reporting results from randomized controlled trials with recurrent events.

BACKGROUND: Evidence-based medicine has been advanced by the use of standards for reporting the design and methodology of randomized controlled trials (RCT). Indeed, without this information it is difficult to assess the quality of evidence from an RCT. Although a variety of statistical methods are available for the analysis of recurrent events, reporting the effect of an intervention on outcomes that recur is an area that remains poorly understood in clinical research. The purpose of this paper is to outline guidelines for reporting results from RCTs where the outcome of interest is a recurrent event. METHODS: We used a simulation study to relate an event process and results from analyses of the gamma-Poisson, independent-increment, conditional, and marginal Cox models. We reviewed the utility of regression models for the rate of a recurrent event by articulating the associated study questions, preenting the risk sets, and interpreting the regression coefficients. RESULTS: Based on a single data set produced by simulation, we reported and contrasted results from statistical methods for evaluating treatment effect from an RCT with a recurrent outcome. We showed that each model has different study questions, assumptions, risk sets, and rate ratio interpretation, and so inferences should consider the appropriateness of the model for the RCT. CONCLUSION: Our guidelines for reporting results from an RCT involving a recurrent event suggest that the study question and the objectives of the trial, such as assessing comparable groups and estimating effect size, should determine the statistical methods. The guidelines should allow clinical researchers to report appropriate measures from an RCT for understanding the effect of intervention on the occurrence of a recurrent event.

Delay in admission for elective coronary-artery bypass grafting is associated with increased in-hospital mortality.

BACKGROUND: Many health care systems now use priority wait lists for scheduling elective coronary artery bypass grafting (CABG) surgery, but there have not yet been any direct estimates of reductions in in-hospital mortality rate afforded by ensuring that the operation is performed within recommended time periods. METHODS: We used a population-based registry to identify patients with established coronary artery disease who underwent isolated CABG in British Columbia, Canada. We studied whether postoperative survival during hospital admission for CABG differed significantly among patients who waited for surgery longer than the recommended time, 6 weeks for patients needing semi-urgent surgery and 12 weeks for those needing non-urgent surgery. RESULTS: Among 7316 patients who underwent CABG, 97 died during the same hospital admission, for a province-wide death rate at discharge of 1.3%. The observed proportion of patients who died during the same admission was 1.0% (27 deaths among 2675 patients) for patients treated within the recommended time and 1.5% (70 among 4641) for whom CABG was delayed. After adjustment for age, sex, anatomy, comorbidity, calendar period, hospital, and mode of admission, patients with early CABG were only 2/3 as likely as those for whom CABG was delayed to experience in-hospital death (odds ratio 0.61; 95% confidence interval [CI] 0.39 to 0.96). There was a linear trend of 5% increase in the odds of in-hospital death for every additional month of delay before surgery, adjusted OR = 1.05 (95% CI 1.00 to 1.11). CONCLUSION: We found a significant survival benefit from performing surgical revascularization within the time deemed acceptable to consultant surgeons for patients requiring the treatment on a semi-urgent or non-urgent basis.