Domperidone increases harmful cardiac events in Parkinson's disease: A Bayesian re-analysis of an observational study.

OBJECTIVES: To assess the risks of ventricular tachyarrhythmia/sudden cardiac death (VT/SCD) with domperidone use in Parkinson's disease (PD). STUDY DESIGNS AND SETTINGS: Using Bayesian methods, results from an observationalstudy were combined with prior beliefs to calculate posterior probabilities of increasedrelative risk (RR)) of VT/SCD with use of domperidone compared to non-use and ofharm, defined as risk exceeding 15%. The analyses were carried with normallydistributed priors (log (RR)): uninformative (N(0,10)) or informative (N(0.53,179)),derived from a meta-analysis (OR (95%CI):1.70 (1.47-1.97)). Sensitivity analyses used:different priors' strengths, different priors, and Bayesian meta-analysis RESULTS: The uninformative prior yielded a RR: 1.23 (95% credible interval (CrI):0.94-1.62), like the published frequentist RR: 1.22 (95% CI:0.99-1.50), with 69% probabilityof harm. With an informative prior weighted at 100%, 50% and 10%, the RR were 1.63(1.41-1.88), 1.57 (1.31-1.91) and 1.39 (1.10-1.93), respectively. The correspondingprobabilities of harm were 100%, 99%, and 94%, respectively. CONCLUSION: While both the frequentist and Bayesian approaches with anuninformative prior were unable to reach a definitive conclusion concerning thearrhythmic risk of domperidone in PD patients, the Bayesian analysis with informativepriors showed a high probability of increased risk that was robust to multiple priorsensitivity analyses.

Higher psychological distress in patients seeking care for a knee disorder is associated with diagnostic discordance between health care providers: a secondary analysis of a diagnostic concordance study.

BACKGROUND: Knee disorders are highly prevalent and may be a disabling condition. An accurate diagnosis is necessary to guide toward a rapid and efficient management of knee disorders. However, the ability to make a valid diagnosis is often complex for clinicians and evidence is mainly focused on clinician cognitive biases or errors produced during clinical reasoning. The aim of this secondary exploratory analysis is to identify patient-specific characteristics associated with diagnostic discordance between health care providers in making a diagnosis for a new knee disorder. METHODS: We performed a secondary analysis of a diagnostic study comparing the diagnostic ability of a physiotherapist to medical musculoskeletal specialists. Patients' socio-demographic, psychosocial and clinical characteristics were compared between the concordant and discordant diagnostic groups. Psychosocial symptoms were evaluated using the validated Kessler 6 (K6) questionnaire. We performed multivariable logistic regressions using the Bayesian Information Criterion to identify the most probable model including patients' characteristics associated with diagnostic discordance. Overall probability of identified variables to explain diagnostic discordance and associated odd ratios (OR) with 95% credibility intervals (95% CrI) were calculated. RESULTS: Overall, 279 participants were evaluated by a physiotherapist and medical musculoskeletal specialists. The mean age of the participants was 49.1 ± 15.8 years and 57.7% were female. The most common disorder was osteoarthritis (n = 117, 18.8% of cases were discordant). The most probable model explaining diagnostic discordance (11.13%) included having depressive symptoms, which was associated with an increased probability of diagnostic discordance (OR: 3.9; 95% CrI: 1.9 - 8.0) and having a higher number of comorbidities, which was associated with a decreased probability of diagnostic discordance (OR: 0.6; 95% CrI: 0.5 - 0.9). The depression item of the K6 questionnaire had a 99.4% chance to be included in a model explaining diagnostic discordance. Other variables taken separately had less than 50% chance to be included in a model explaining diagnostic discordance and cannot be considered significant. CONCLUSION: Our results suggest that depressive symptoms may increase the risk of knee diagnostic discordance. Clinicians may be more likely to make diagnostic errors and should be more cautious when evaluating patients with knee disorders suffering from psychological distress.

Immediate vs Delayed Stenting in ST-Elevation Myocardial Infarction: Rationale and Design of the International PRIMACY Bayesian Randomized Controlled Trial.

BACKGROUND: Primary percutaneous coronary intervention is used to restore blood flow in the infarct-related coronary artery, followed by immediate stenting to prevent reocclusion. Stents implanted in thrombus-laden arteries cause distal embolization, which paradoxically impairs myocardial reperfusion and ventricular function. Whether a strategy of delayed stenting improves outcomes in patients with acute ST-elevation myocardial infarction (STEMI) is uncertain. METHODS: The Primary Reperfusion Secondary Stenting (PRIMACY) is a Bayesian prospective, randomized, open-label, blinded end point trial in which delayed vs immediate stenting in patients with STEMI were compared for prevention of cardiovascular death, nonfatal myocardial infarction, heart failure, or unplanned target vessel revascularization at 9 months. All participants were immediately reperfused, but those assigned to the delayed arm underwent stenting after an interval of 24 to 48 hours. This interval was bridged with antithrombin therapy to reduce thrombus burden. In the principal Bayesian hierarchical random effects analysis, data from exchangeable trials will be combined into a study prior and updated with PRIMACY into a posterior probability of efficacy. RESULTS: A total of 305 participants were randomized across 15 centres in France and Canada between April 2014 and September 2017. At baseline, the median age of participants was 59 years, 81% were male, and 3% had a history of percutaneous coronary intervention. Results from PRIMACY will be updated from the patient-level data of 1568 participants enrolled in the Deferred Stent Trial in STEMI (DEFER; United Kingdom), Minimalist Immediate Mechanical Intervention (MIMI; France), Danish Trial in Acute Myocardial Infarction-3 (DANAMI-3; Denmark), and Impact of Immediate Stent Implantation Versus Deferred Stent Implantation on Infarct Size and Microvascular Perfusion in Patients With ST Segment-Elevation Myocardial Infarction (INNOVATION, South Korea) trials. CONCLUSIONS: We expect to clarify whether delayed stenting can safely reduce the occurrence of adverse cardiovascular end points compared with immediate stenting in patients with STEMI.

Bayesian consensus-based sample size criteria for binomial proportions.

Many sample size criteria exist. These include power calculations and methods based on confidence interval widths from a frequentist viewpoint, and Bayesian methods based on credible interval widths or decision theory. Bayesian methods account for the inherent uncertainty of inputs to sample size calculations through the use of prior information rather than the point estimates typically used by frequentist methods. However, the choice of prior density can be problematic because there will almost always be different appreciations of the past evidence. Such differences can be accommodated a priori by robust methods for Bayesian design, for example, using mixtures or ϵ-contaminated priors. This would then ensure that the prior class includes divergent opinions. However, one may prefer to report several posterior densities arising from a "community of priors," which cover the range of plausible prior densities, rather than forming a single class of priors. To date, however, there are no corresponding sample size methods that specifically account for a community of prior densities in the sense of ensuring a large-enough sample size for the data to sufficiently overwhelm the priors to ensure consensus across widely divergent prior views. In this paper, we develop methods that account for the variability in prior opinions by providing the sample size required to induce posterior agreement to a prespecified degree. Prototypic examples to one- and two-sample binomial outcomes are included. We compare sample sizes from criteria that consider a family of priors to those that would result from previous interval-based Bayesian criteria.

Pneumococcal pneumonia prevalence among adults with severe acute respiratory illness in Thailand - comparison of Bayesian latent class modeling and conventional analysis.

BACKGROUND: Determining the etiology of pneumonia is essential to guide public health interventions. Diagnostic test results, including from polymerase chain reaction (PCR) assays of upper respiratory tract specimens, have been used to estimate prevalence of pneumococcal pneumonia. However limitations in test sensitivity and specificity and the specimen types available make establishing a definitive diagnosis challenging. Prevalence estimates for pneumococcal pneumonia could be biased in the absence of a true gold standard reference test for detecting Streptococcus pneumoniae. METHODS: We conducted a case control study to identify etiologies of community acquired pneumonia (CAP) from April 2014 through August 2015 in Thailand. We estimated the prevalence of pneumococcal pneumonia among adults hospitalized for CAP using Bayesian latent class models (BLCMs) incorporating results of real-time polymerase chain reaction (qPCR) testing of upper respiratory tract specimens and a urine antigen test (UAT) from cases and controls. We compared the prevalence estimate to conventional analyses using only UAT as a reference test. RESULTS: The estimated prevalence of pneumococcal pneumonia was 8% (95% CI: 5-11%) by conventional analyses. By BLCM, we estimated the prevalence to be 10% (95% CrI: 7-16%) using binary qPCR and UAT results, and 11% (95% CrI: 7-17%) using binary UAT results and qPCR cycle threshold (Ct) values. CONCLUSIONS: BLCM suggests a > 25% higher prevalence of pneumococcal pneumonia than estimated by a conventional approach assuming UAT as a gold standard reference test. Higher quantities of pneumococcal DNA in the upper respiratory tract were associated with pneumococcal pneumonia in adults but the addition of a second specific pneumococcal test was required to accurately estimate disease status and prevalence. By incorporating the inherent uncertainty of diagnostic tests, BLCM can obtain more reliable estimates of disease status and improve understanding of underlying etiology.

The Measurable Benefits of a Workplace Wellness Program in Canada: Results After One Year.

OBJECTIVE: The aim of this study was to evaluate the impact of an employee wellness program in Canada. METHODS: A comprehensive program including web-based lifestyle challenges was evaluated with annual health screenings. RESULTS: Among 730 eligible employees, 688 (94%) registered for the program, 571 (78%) completed a health screening at baseline, and 314 (43%) at 1 year. Most (66%) employees tracked their activity for more than 6 weeks. At 1-year follow-up, there were significant clinical improvements in systolic blood pressure -3.4 mm Hg, and reductions in poor sleep quality (33% to 28%), high emotional stress (21% to 15%), and fatigue (11% to 6%). A positive dose-response was noted where the greatest improvements were observed among those who participated the most. CONCLUSION: The program had high employee engagement. After 1 year, the benefits included clinically important improvements in physical and mental health.

Clinically Apparent Arterial Thrombosis in Persons with Systemic Vasculitis.

OBJECTIVE: To estimate the incidence rate of clinically apparent arterial thrombotic events and associated comorbidities in patients with primary systemic vasculitis. METHODS: Using large cohort administrative data from Quebec, Canada, we identified patients with vasculitis, including polyarteritis nodosa (PAN) and granulomatosis with polyangiitis (GPA). Incident acute myocardial infarctions (AMIs) and cerebrovascular accidents (CVAs) after the diagnosis of vasculitis were ascertained in the PAN and GPA group via billing and hospitalization data. These were compared to rates of a general population comparator group. The incidences of comorbidities (type 2 diabetes mellitus, dyslipidemia, and hypertension) were also collected. RESULTS: Among the 626 patients identified with vasculitis, 19.7% had PAN, 2.9% had Kawasaki disease, 23.8% had GPA, 52.4% had GCA, and 1.3% had Takayasu arteritis. The AMI rate was substantially higher in males aged 18-44 with PAN, with rates up to 268.1 events per 10,000 patient years [95% CI 67.1-1070.2], approximately 30 times that in the age- and sex-matched control group. The CVA rate was also substantially higher, particularly in adults aged 45-65. Patients with vasculitis had elevated incidences of diabetes, dyslipidemia, and hypertension versus the general population. CONCLUSION: Atherothrombotic rates were elevated in patients identified as having primary systemic vasculitis. While incident rates of cardiovascular comorbidities were also increased, the substantial elevation in AMIs seen in young adults suggests a disease-specific component which requires further investigation.

Fine particulate air pollution and systemic autoimmune rheumatic disease in two Canadian provinces.

OBJECTIVE: To estimate the degree to which fine particulate (PM2.5) air pollution is associated with systemic autoimmune rheumatic diseases (SARDs). METHODS: We used population-based administrative data from Alberta (1993-2007) and Quebec (1989-2011). SARD algorithms included ≥2 physician billing codes, or ≥1 rheumatology billing code, or ≥1 hospitalization diagnostic code (for systemic lupus, Sjogren's Syndrome, scleroderma, polymyositis, dermatomyositis, or undifferentiated connective tissue disease). Bayesian hierarchical latent class regression models estimated the probability that any given resident was a SARD case, based on the algorithms. Mean 2001-2006 residential ambient PM2.5 levels were assigned using satellite-derived data for dissemination area regions in Alberta and CLSC regions in Quebec. The sum of individual level probabilities provided the estimated total cases per region in each province, according to age, sex, urban-versus-rural residence, income, and PM2.5 levels. In Alberta, we ran separate models for First-Nations (FN) and non-First Nations subgroups. Bayesian logistic regression modeling generated odds ratio (OR) estimates for being a SARD case, accounting concurrently for demographics, as well as an interaction term between age and sex. RESULTS: Our data suggested that the probability of being a SARD case was higher among females versus males and for residents aged >45 versus younger, with the highest ORs for older females. Independently, the odds of being a SARDs case increased with PM2.5 levels in both provinces. CONCLUSION: Our data suggest that PM2.5 exposure may be associated with an increased risk of SARDs.

Associations between neighbourhood walkability and daily steps in adults: a systematic review and meta-analysis.

BACKGROUND: Higher street connectivity, land use mix and residential density (collectively referred to as neighbourhood walkability) have been linked to higher levels of walking. The objective of our study was to summarize the current body of knowledge on the association between neighbourhood walkability and biosensor-assessed daily steps in adults. METHODS: We conducted a systematic search of PubMed, SCOPUS, and Embase (Ovid) for articles published prior to May 2014 on the association between walkability (based on Geographic Information Systems-derived street connectivity, land use mix, and/or residential density) and daily steps (pedometer or accelerometer-assessed) in adults. The mean differences in daily steps between adults living in high versus low walkable neighbourhoods were pooled across studies using a Bayesian hierarchical model. RESULTS: The search strategy yielded 8,744 unique abstracts. Thirty of these underwent full article review of which six met the inclusion criteria. Four of these studies were conducted in Europe and two were conducted in Asia. A meta-analysis of four of these six studies indicates that participants living in high compared to low walkable neighbourhoods accumulate 766 more steps per day (95 % credible interval 250, 1271). This accounts for approximately 8 % of recommended daily steps. CONCLUSIONS: The results of European and Asian studies support the hypothesis that higher neighbourhood walkability is associated with higher levels of biosensor-assessed walking in adults. More studies on this association are needed in North America.

Fine particulate air pollution, nitrogen dioxide, and systemic autoimmune rheumatic disease in Calgary, Alberta.

OBJECTIVE: To estimate the association between fine particulate (PM2.5) and nitrogen dioxide (NO2) pollution and systemic autoimmune rheumatic diseases (SARDs). METHODS: Associations between ambient air pollution (PM2.5 and NO2) and SARDs were assessed using land-use regression models for Calgary, Alberta and administrative health data (1993-2007). SARD case definitions were based on ≥2 physician claims, or ≥1 rheumatology billing code; or ≥1 hospitalization code (for systemic lupus, Sjogren's Syndrome, scleroderma, polymyositis, dermatomyositis, or undifferentiated connective tissue disease). Bayesian hierarchical latent class regression models estimated the probability that each resident was a SARD case, based on these case definitions. The sum of individual level probabilities provided the estimated number of cases in each area. The latent class model included terms for age, sex, and an interaction term between age and sex. Bayesian logistic regression models were used to generate adjusted odds ratios (OR) for NO2 and PM2.5. pollutant models, adjusting for neighbourhood income, age, sex, and an interaction between age and sex. We also examined models stratified for First-Nations (FN) and non-FN subgroups. RESULTS: Residents that were female and/or aged >45 had a greater probability of being a SARD case, with the highest OR estimates for older females. Independently, the odds of being a SARDs case increased with PM2.5 levels, but the results were inconclusive for NO2. The results stratified by FN and non-FN groups were not distinctly different. CONCLUSION: In this urban Canadian sample, adjusting for demographics, exposure to PM2.5 was associated with an increased risk of SARDs. The results for NO2 were inconclusive.

Estimating risk of emergency room visits for asthma from personal versus fixed site measurements of NO2.

BACKGROUND: We examined the impact of data source and exposure measurement error for ambient NO2 on risk estimates derived from a case-crossover study of emergency room visits for asthma in Windsor, Canada between 2002 and 2009. METHODS: Paired personal and fixed-site NO2 data were available from an independent population (47 children and 48 adults) in Windsor between 2005 and 2006. We used linear regression to estimate the relationship and measurement error variance induced between fixed site and personal measurements of NO2, and through a series of simulations, evaluated the potential for a Bayesian model to adjust for this change in scale and measurement error. Finally, we re-analyzed data from the previous case-crossover study adjusting for the estimated change in slope and measurement error. RESULTS: Correlations between paired NO2 measurements were weak (R(2)≤0.08) and slopes were far from unity (0.0029≤ß≤0.30). Adjusting the previous case-crossover analysis suggested a much stronger association between personal NO2 (per 1ppb) (Odds Ratio (OR)=1.276, 95% Credible Interval (CrI): 1.034, 1.569) and emergency room visits for asthma among children relative to the fixed-site estimate (OR=1.024, 95% CrI 1.004-1.045). CONCLUSIONS: Our findings suggest that risk estimates based on fixed-site NO2 concentrations may differ substantially from estimates based on personal exposures if the change in scale and/or measurement error is large. In practice, one must always keep the scale being used in mind when interpreting risk estimates and not assume that coefficients for ambient concentrations reflect risks at the personal level.

The prevalence of systemic autoimmune rheumatic diseases in Canadian pediatric populations: administrative database estimates.

To estimate systemic autoimmune rheumatic disease (SARD) prevalence using administrative data for pediatric populations in four Canadian provinces. Physician billing claims and inpatient hospitalizations from Alberta, Manitoba, Quebec, and Saskatchewan were used to define cases aged ≤18 years with a SARD diagnosis code in: one or more hospitalization, two or more physician visits within 2 years and at least 2 months apart, or one or more physician visit to a rheumatologist. Estimates ranged from 15.9/100,000 in Quebec [95% confidence interval (95% CI) 14.1, 18.0] to 23.0/100,000 in Manitoba (95% CI 17.9, 29.2). SARDs were more common in females than in males across all provinces. There was a slightly higher prevalence among those living in urban compared to rural areas of Alberta (rate difference 14.4, 95% CI 8.6, 20.1) and Saskatchewan (rate difference 13.8, 95% CI 1.0, 26.6). Our results provide population-based prevalence estimates of pediatric SARDs in four Canadian provinces.

Electrocardiographic findings in systemic lupus erythematosus: data from an international inception cohort.

OBJECTIVE: To estimate the early prevalence of various electrocardiographic (EKG) abnormalities in patients with systemic lupus erythematosus (SLE) and to evaluate possible associations between repolarization changes (increased corrected QT [QTc] and QT dispersion [QTd]) and clinical and laboratory variables, including the anti-Ro/SSA level and specificity (52 or 60 kd). METHODS: We studied adult SLE patients from 19 centers participating in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Registry. Demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]), disease damage (SLICC/American College of Rheumatology Damage Index [SDI]), and laboratory data from the baseline or first followup visit were assessed. Multivariate logistic and linear regression models were used to asses for any cross-sectional associations between anti-Ro/SSA and EKG repolarization abnormalities. RESULTS: For the 779 patients included, mean ± SD age was 35.2 ± 13.8 years, 88.4% were women, and mean ± SD disease duration was 10.5 ± 14.5 months. Mean ± SD SLEDAI-2K score was 5.4 ± 5.6 and mean ± SD SDI score was 0.5 ± 1.0. EKG abnormalities were frequent and included nonspecific ST-T changes (30.9%), possible left ventricular hypertrophy (5.4%), and supraventricular arrhythmias (1.3%). A QTc ≥440 msec was found in 15.3%, while a QTc ≥460 msec was found in 5.3%. Mean ± SD QTd was 34.2 ± 14.7 msec and QTd ≥40 msec was frequent (38.1%). Neither the specificity nor the level of anti-Ro/SSA was associated with QTc duration or QTd, although confidence intervals were wide. Total SDI was significantly associated with a QTc interval exceeding 440 msec (odds ratio 1.38 [95% confidence interval 1.06, 1.79]). CONCLUSION: A substantial proportion of patients with recent-onset SLE exhibited repolarization abnormalities, although severe abnormalities were rare.

Chronic inflammatory arthritis prevalence estimates for children and adolescents in three Canadian provinces.

There is a paucity of published population-based estimates of the prevalence of chronic inflammatory arthritis in the pediatric population. We used administrative health data to estimate the prevalence of chronic inflammatory arthritis in individuals ≤18 years in three Canadian provinces: Quebec, Manitoba, and Saskatchewan. Cases aged ≤18 years were identified by meeting any one of the following criteria: (a) ≥1 hospital discharge abstract with an ICD-9 code of 714 or ICD-10-CA codes of M05, M06 or M08, or (b) ≥2 ICD-9 714 billing codes ≥8 weeks apart, but within 2 years, or (c) ≥1 ICD-9 714 billing code by a rheumatologist. Crude prevalence estimates per 10,000 population were estimated with 95 % confidence intervals (CIs). Prevalence estimates were 11.7 per 10,000 individuals ≤18 years of age in Manitoba, 9.8 per 10,000 in Saskatchewan, and 8.0 per 10,000 in Quebec. In pairwise comparisons of rate differences, Manitoba and Saskatchewan had higher estimates than Quebec. Prevalence estimates were higher for females than males, with a difference of 5.9 cases per 10,000 residents (95 % CI 5.1, 6.7). Saskatchewan was the only province with a higher estimate in urban compared to rural residents (5.2, 95 % CI 2.5, 8.0). Variations in provincial estimates may be due to differences in underlying population characteristics. Although these estimates have face validity and are in keeping with the range of previously published pediatric prevalence estimates, studies to establish the empiric validity of case-finding algorithms are needed to advance research in pediatric chronic disease epidemiology.

Rheumatoid arthritis prevalence in Quebec.

BACKGROUND: To estimate rheumatoid arthritis (RA) prevalence in Quebec using administrative health data, comparing across regions. METHODS: Cases of RA were ascertained from physician billing and hospitalization data, 1992-2008. We used three case definitions: 1) ≥ 2 billing diagnoses, submitted by any physician, ≥ 2 months apart, but within 2 years; 2) ≥ 1 diagnosis, by a rheumatologist; 3) ≥1 hospitalization diagnosis (all based on ICD-9 code 714, and ICD-10 code M05). We combined data across these three case definitions, using Bayesian hierarchical latent class models to estimate RA prevalence, adjusting for the imperfect sensitivity and specificity of the data. We compared urban versus rural regions. RESULTS: Using our case definitions and no adjustment for error, we defined 75,760 cases for an over-all RA prevalence of 9.9 per thousand residents. After adjusting for the imperfect sensitivity and specificity of our case definition algorithms, we estimated Quebec RA prevalence at 5.6 per 1000 females and 4.1 per 1000 males. The adjusted RA prevalence estimates for older females were the highest for any demographic group (9.9 cases per 1,000), and were similar in rural and urban regions. In younger males and females, and in older males, RA prevalence estimates were lower in rural versus urban areas. CONCLUSIONS: Without adjustment for error inherent in administrative databases, RA prevalence in Quebec was approximately 1%, while adjusted estimates are approximately half that. The lower prevalence in rural areas, seen for most demographic groups, may suggest either true regional variations in RA risk, or under-ascertainment of cases in rural Quebec.

Systemic autoimmune rheumatic disease prevalence in Canada: updated analyses across 7 provinces.

OBJECTIVE: To estimate systemic autoimmune rheumatic disease (SARD) prevalence across 7 Canadian provinces using population-based administrative data evaluating both regional variations and the effects of age and sex. METHODS: Using provincial physician billing and hospitalization data, cases of SARD (systemic lupus erythematosus, scleroderma, primary Sjögren syndrome, polymyositis/dermatomyositis) were ascertained. Three case definitions (rheumatology billing, 2-code physician billing, and hospital diagnosis) were combined to derive a SARD prevalence estimate for each province, categorized by age, sex, and rural/urban status. A hierarchical Bayesian latent class regression model was fit to account for the imperfect sensitivity and specificity of each case definition. The model also provided sensitivity estimates of different case definition approaches. RESULTS: Prevalence estimates for overall SARD ranged between 2 and 5 cases per 1000 residents across provinces. Similar demographic trends were evident across provinces, with greater prevalence in women and in persons over 45 years old. SARD prevalence in women over 45 was close to 1%. Overall sensitivity was poor, but estimates for each of the 3 case definitions improved within older populations and were slightly higher for men compared to women. CONCLUSION: Our results are consistent with previous estimates and other North American findings, and provide results from coast to coast, as well as useful information about the degree of regional and demographic variations that can be seen within a single country. Our work demonstrates the usefulness of using multiple data sources, adjusting for the error in each, and providing estimates of the sensitivity of different case definition approaches.

Bayesian sample size determination for case-control studies when exposure may be misclassified.

Odds ratios are frequently used for estimating the effect of an exposure on the probability of disease in case-control studies. In planning such studies, methods for sample size determination are required to ensure sufficient accuracy in estimating odds ratios once the data are collected. Often, the exposure used in epidemiologic studies is not perfectly ascertained. This can arise from recall bias, the use of a proxy exposure measurement, uncertain work exposure history, and laboratory or other errors. The resulting misclassification can have large impacts on the accuracy and precision of estimators, and specialized estimation techniques have been developed to adjust for these biases. However, much less work has been done to account for the anticipated decrease in the precision of estimators at the design stage. Here, we develop methods for sample size determination for odds ratios in the presence of exposure misclassification by using several interval-based Bayesian criteria. By using a series of prototypical examples, we compare sample size requirements after adjustment for misclassification with those required when this problem is ignored. We illustrate the methods by planning a case-control study of the effect of late introduction of peanut to the diet of children to the subsequent development of peanut allergy.

Time variability of C-reactive protein: implications for clinical risk stratification.

BACKGROUND: C-reactive protein (CRP) is proposed as a screening test for predicting risk and guiding preventive approaches in coronary artery disease (CAD). However, the stability of repeated CRP measurements over time in subjects with and without CAD is not well defined. We sought to determine the stability of serial CRP measurements in stable subjects with distinct CAD manifestations and a group without CAD while carefully controlling for known confounders. METHODS: We prospectively studied 4 groups of 25 stable subjects each 1) a history of recurrent acute coronary events; 2) a single myocardial infarction ≥7 years ago; 3) longstanding CAD (≥7 years) that had never been unstable; 4) no CAD. Fifteen measurements of CRP were obtained to cover 21 time-points: 3 times during one day; 5 consecutive days; 4 consecutive weeks; 4 consecutive months; and every 3 months over the year. CRP risk threshold was set at 2.0 mg/L. We estimated variance across time-points using standard descriptive statistics and Bayesian hierarchical models. RESULTS: Median CRP values of the 4 groups and their pattern of variability did not differ substantially so all subjects were analyzed together. The median individual standard deviation (SD) CRP values within-day, within-week, between-weeks and between-months were 0.07, 0.19, 0.36 and 0.63 mg/L, respectively. Forty-six percent of subjects changed CRP risk category at least once and 21% had ≥4 weekly and monthly CRP values in both low and high-risk categories. CONCLUSIONS: Considering its large intra-individual variability, it may be problematic to rely on CRP values for CAD risk prediction and therapeutic decision-making in individual subjects.

Association of smoking with cutaneous manifestations in systemic lupus erythematosus.

OBJECTIVE: To examine the association between smoking and cutaneous involvement in systemic lupus erythematosus (SLE). METHODS: We analyzed data from a multicenter Canadian SLE cohort. Mucocutaneous involvement was recorded at the most recent visit using the Systemic Lupus Erythematosus Disease Activity Index 2000 Update (rash, alopecia, and oral ulcers), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (alopecia, extensive scarring, and skin ulceration), and the ACR revised criteria for SLE (malar rash, discoid rash, photosensitivity, and mucosal involvement). Multivariate logistic regression models were used to estimate the independent association between mucocutaneous involvement and cigarette smoking, age, sex, ethnicity, lupus duration, medications, and laboratory data. RESULTS: In our cohort of 1,346 patients (91.0% women), the mean ± SD age was 47.1 ± 14.3 years and the mean ± SD disease duration was 13.2 ± 10.0 years. In total, 41.2% of patients were ever smokers, 14.0% current smokers, and 27.1% past smokers. Active mucocutaneous manifestations occurred in 28.4% of patients; cutaneous damage occurred in 15.4%. Regarding the ACR criteria, malar rash was noted in 59.5%, discoid rash in 16.9%, and photosensitivity in 55.7% of patients. In the multivariate analysis, current smoking was associated with active SLE rash (odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.07, 2.48]). Having ever smoked was associated with ACR discoid rash (OR 2.36 [95% CI 1.69, 3.29]) and photosensitivity (OR 1.47 [95% CI 1.11, 1.95]), and with the ACR total cutaneous score (OR 1.50 [95% CI 1.22, 1.85]). We did not detect any associations between previous smoking and active cutaneous manifestations. No association was found between smoking and cutaneous damage or mucosal ulcers. No interaction was seen between smoking and antimalarials. CONCLUSION: Current smoking is associated with active SLE rash, and ever smoking with the ACR total cutaneous score. This provides additional motivation for smoking cessation in SLE.

Personal exposure to specific volatile organic compounds and acute changes in lung function and heart rate variability among urban cyclists.

BACKGROUND: Few studies have examined the acute cardiorespiratory effects of specific volatile organic compound (VOC) exposures from traffic pollution. METHODS: A cross-over study was conducted among 42 healthy adults during summer 2010 in Ottawa, Canada. Participants cycled for 1-h along high and low-traffic routes and VOC exposures were determined along each route. Lung function, exhaled nitric oxide, and heart rate variability were monitored before cycling and 1-4h after the start of cycling. Bayesian hierarchical models were used to examine the relationship between 26 VOCs and acute changes in clinical outcomes adjusted for potential confounding factors. RESULTS: Each inter-quartile range (IQR) increase in propane/butane exposure was associated with a 2.0 millisecond (ms) (95% CI: 0.65, 3.2) increase in SDNN (standard deviation of normal-to-normal intervals), a 24 ms(2) (95% CI: 6.6, 41) increase in HF (high frequency power), and a 65 ms(2) (95% CI: 11, 118) increase in LF (low frequency power) in the hours following cycling. IQR increases in ethane and isoprene were associated with a 5.8 ms (95% CI: -9.8, -1.7): decrease in SDNN and a 24 ms(2) (95% CI: -44, -7.9) decrease in HF, respectively. IQR increases in benzene exposure were associated with a 1.7 ppb (95% CI: 1.1, 2.3) increase in exhaled nitric oxide and each IQR increase in 3-methylhexane exposure was associated with a 102 mL (95% CI: -157, -47) decrease in forced expiratory volume in 1-s. CONCLUSIONS: Exposure to traffic-related VOCs may contribute to acute changes in lung function, inflammation, or heart rate variability.