Michal Abrahamowicz

Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus

OBJECTIVE The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors. METHODS The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individuals risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques. RESULTS Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8-15.6), 17.0 for death due to CHD (95% CI 8.1-29.7), 7.5 for overall CHD (95% CI 5.1-10.4), and 7.9 for stroke (95% CI 4.0-13.6). CONCLUSION There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.

Development of a Model for Training and Evaluation of Laparoscopic Skills

BACKGROUND Interest in the training and evaluation of laparoscopic skills is extending beyond the realm of the operating room to the use of laparoscopic simulators. The purpose of this study was to develop a series of structured tasks to objectively measure laparoscopic skills. This model was then used to test for the effects of level of training and practice on performance. METHODS Forty-two subjects (6 each of surgical residents PGY1 to PGY5, 6 surgeons who practice laparoscopy and 6 who do not) were evaluated. Each subject viewed a 20-minute introductory video, then was tested performing 7 laparoscopic tasks (peg transfers, pattern cutting, clip and divide, endolooping, mesh placement and fixation, suturing with intracorporeal or extracorporeal knots). Performance was measured using a scoring system rewarding precision and speed. Each candidate repeated all 7 tasks and was rescored. Data were analyzed by linear regression to assess the relationship of performance with level of residency training for each task, and by ANOVA with repeated measures to test for effects of level of training, of repetition, and of the interaction between level of training and repetition on overall performance. Students t test was used to evaluate differences between laparoscopic and nonlaparoscopic surgeons and between each of these groups and the PGY 5 level of surgical residents. RESULTS Significant predictors of overall performance were (a) level of training (P = 0.002), (b) repetition (P < 0.0001), and (c) interaction between level of training and practice (P = 0.001). There was also a significant interaction between level of training and the specific task on performance scores (P = 0.006). When each task was evaluated individually for the 30 residents, 4 of the 7 tasks (tasks 1, 2, 6, 7) showed significant correlation between PGY level and score. A significant difference in performance scores between laparoscopic and nonlaparoscopic surgeons was seen for tasks 1, 2, and 6. CONCLUSIONS A model was developed to evaluate laparoscopic skills. Construct validity was demonstrated by measuring significant improvement in performance with increasing residency training, and with practice. Further validation will require correlation of performance in the model with skill in vivo.

Changing Mortality in Congenital Heart Disease

OBJECTIVES This study sought to characterize temporal trends in all-cause mortality in patients with congenital heart disease (CHD). BACKGROUND Historically, most deaths in patients with CHD occurred in early childhood. Notable advances have since been achieved that may impact on mortality trends. METHODS We conducted a population-based cohort study of patients with CHD in Quebec, Canada, from July 1987 to June 2005. A total of 8,561 deaths occurred in 71,686 patients with CHD followed for 982,363 patient-years. RESULTS The proportion of infant and childhood deaths markedly declined from 1987 to 2005, with a reduction in mortality that exceeded that of the general population. Distribution of age at death transitioned from a bimodal to unimodal, albeit skewed, pattern, more closely approximating the general population. Overall, mortality decreased by 31% (mortality rate ratio: 0.69, 95% confidence interval [CI]: 0.61 to 0.79) in the last (2002 to 2005) relative to the first (1987 to 1990) period of observation. Mortality rates decreased in all age groups below 65 years, with the largest reduction in infants (mortality rate ratio: 0.23, 95% CI: 0.12 to 0.47). In adults 18 to 64 years, the mortality reduction (mortality rate ratio: 0.84, 95% CI: 0.73 to 0.97) paralleled the general population. Gains in survival were mostly driven by reduced mortality in severe forms of CHD, particularly in children (mortality rate ratio: 0.33, 95% CI: 0.19 to 0.60), and were consistent across most subtypes. CONCLUSIONS Deaths in CHD have shifted away from infants and towards adults, with a steady increase in age at death and decreasing mortality.

Overview of the Reanalysis of the Harvard Six Cities Study and American Cancer Society Study of Particulate Air Pollution and Mortality

This article provides an overview of the Reanalysis Study of the Harvard Six Cities and the American Cancer Society (ACS) studies of particulate air pollution and mortality. The previous findings of the studies have been subject to debate. In response, a reanalysis team, comprised of Canadian and Amercian researchers, was invited to participate in an independent reanalysis project to address the concerns. Phase I of the reanalysis involved the design of data audits to determine whether each study conformed to the consistency and accuracy of their data. Phase II of the reanalysis involved conducting a series of comprehensive analyses using alternative statistical methods. Alternative models were also used to identify covariates that may confound or modify the association of particulate air pollution as well as identify sensitive population subgroups. The audit demonstrated that the data in the original analyses were of high quality, as were the risk estimates reported by the original investigators. The sensitivity analysis illustrated that the mortality risk estimates reported in both studies were found to be robust against alternative Cox models. Detailed investigation of the covariate effects found a significant modifying effect of education and a relative risk of mortality associated with fine particles and declining education levels. The study team applied spatial analytic methods to the ACS data, resulting in various levels of spatial autocorrelations supporting the reported association for fine particles mortality of the original investigators as well as demonstrating a significant association between sulfur dioxide and mortality. Collectively, our reanalysis suggest that mortality may be attributable to more than one component of the complex mixture of ambient air pollutants for U.S. urban areas.

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

OBJECTIVE To identify in patients with Raynauds phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc-specific autoantibodies. METHODS Consecutive patients referred for evaluation of RP who had no definite connective tissue disease were evaluated for microvascular damage by nailfold capillary microscopy (NCM) and for anticentromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I, and anti-RNA polymerase III (anti-RNAP III) autoantibodies by specific assays. Patients were studied prospectively. RESULTS Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc. A characteristic sequence of microvascular damage was identified, starting with enlarged capillaries, followed by capillary loss, and then by capillary telangiectases. Definite SSc was diagnosed in close temporal relationship to capillary loss. Enlarged capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc. Anti-CENP-B and anti-Th/To antibodies predicted enlarged capillaries; these autoantibodies and anti-RNAP III predicted capillary loss. Each autoantibody was associated with a distinct time course of microvascular damage. At followup, 79.5% of patients with 1 of these autoantibodies and abnormal findings on NCM at baseline had developed definite SSc. Patients with both baseline predictors were 60 times more likely to develop definite SSc. The data validated the proposed criteria for early SSc. CONCLUSION In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SSc-specific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of developing definite SSc, whereas their absence rules out this outcome.

Patient nonadherence to medication in inflammatory bowel disease

OBJECTIVE:The aim of this study was to identify determinants of nonadherence to medication in outpatients with established inflammatory bowel disease (IBD).METHODS:Ten gastroenterologists and 153 of their IBD patients participated in this prospective study. Demographic, clinical, and psychosocial characteristics, as well as patient-physician discordance, were assessed at an office visit. Nonadherence to medication was assessed 2 wk later. Separate generalized estimating equations were used to identify determinants of nonadherence.RESULTS:Physicians averaged 47.9 yr in age (range 30.1–57.5 yr), and 90% were male. Patients averaged 37.0 yr (SD = 15.1), and 87 (56.9%) were female. In all, 63 patients (41.2%) were nonadherent to medication; of these, 51 (81.0%) indicated unintentional nonadherence, 23 (36.5%) intentional nonadherence, and 11 (17.5%) both. Overall nonadherence was predicted by disease activity (OR = 0.55, p = 0.0022), new patient status (OR = 2.14, p = 0.0394), disease duration (OR = 0.50, p = 0.0001), and scheduling a follow-up appointment (OR = 0.30, p = 0.0059), whereas higher discordance on well-being was predictive only in psychologically nondistressed patients (p = 0.0026 for interaction). Unintentional nonadherence was predicted by age (OR = 0.97, p = 0.0072), new patient status (OR = 2.80, p = 0239), and higher discordance on well-being in psychologically nondistressed patients (p = 0.0504). Intentional nonadherence was predicted by disease duration (OR = 0.55, p = 0032), scheduling a follow-up appointment (OR = 0.12, p = 0.0001), certainty that medication would be helpful (OR = 0.99, p = 0.0409), and total patient-physician discordance (OR = 1.59, p = .0120).CONCLUSIONS:These findings suggest that the therapeutic relationship, as well as individual clinical and psychosocial characteristics, influence adherence to medication.

Does hepatitis C virus co-infection accelerate clinical and immunological evolution of Hiv-infected patients?

Objective:To study the influence of hepatitis C virus (HCV) co-infection on clinical and immunological evolution of HIV-infected patients. Design:A longitudinal study of HIV-infected individuals with or without HCV infection, identified at the Infectious Diseases Department of Dijon University Hospital and enrolled in a historical cohort, was performed. Methods:One hundred and nineteen HIV-infected people co-infected with HCV and 119 matched individuals infected with HIV alone were included in the cohort (median participation time 3 years; range, 2 months to 11.5 years). Clinical progression was defined as one or more of the following: a 30% decrease in the Karnofsky index; a 20% loss of body weight; an AIDS-defining illness (for non-AIDS patients); death (except by accident, suicide or overdose). Immunological progression was defined as a 50% decrease in the initial CD4 T-cell count (for patients with an initial count > 100 × 106 cells/l). Effects of HCV co-infection were evaluated using Kaplan-Meier survival analysis and significance was tested using univariate (log-rank and Petos tests) and multivariate methods (Coxs model). Results:In univariate analysis, immunological progression was not statistically different between the HCV-positive group and the HCV-negative group, whereas clinical progression was significantly faster in HCV-positive patients (P < 0.005, log–rank test). In a multivariate Cox model, clinical progression remained significantly associated with infection by HCV [hazard ratio (HR), 1.64; 95% confidence interval (CI), 1.06–2.55; P < 0.05]. Stratified multivariable analysis retained HCV as a significant prognostic factor of clinical progression (HR, 10.9; 95% CI, 1.09–109.3; P < 0.05) and immunological progression (HR, 2.31; 95% CI, 1.16–4.62; P < 0.02) for patients with an initial CD4 count above 600 × 106 cells/l. Conclusions:Clinical progression is more rapid in HIV–HCV co-infected patients than in HIV-seropositive patients are not infected by HCV. The prognostic value of HCV infection for both clinical and immunological progression is significant at early stages of HIV infection. These findings may argue for active management of hepatitis C infection in co-infected individuals, especially for asymptomatic patients whose CD4 count is above 600 × 106 cells/l, to predict and prevent accelerated progression of HCV and HIV diseases.

The Quebec Back Pain Disability Scale: Conceptualization and development

The Quebec Back Pain Disability Scale is a new measure of functional disability for patients with back pain. Functional disability was operationalized in terms of perceived difficulty associated with simple physical activities. The content of the scale was developed in several stages, including a literature review, two studies seeking the opinions of patients and experts, pilot testing, and a large, longitudinal study of back pain patients. Forty-eight disability items were extensively studied using standard methods such as test-retest reliability, item-total correlations, and factor analysis, as well as modern techniques based on item response theory. Items that were highly effective in discriminating between different levels of disability were selected for the final, reduced scale. The scale has 20 items, representing six empirically derived categories of activities affected by back pain. Measurement properties of this instrument have been previously discussed.

Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure

BackgroundEpidemiological studies of exposures that vary with time require an additional level of methodological complexity to account for the time-dependence of exposure. This study compares a nested case-control approach for the study of time-dependent exposure with cohort analysis using Cox regression including time-dependent covariates.MethodsA cohort of 1340 subjects with four fixed and seven time-dependent covariates was used for this study. Nested case-control analyses were repeated 100 times for each of 4, 8, 16, 32, and 64 controls per case, and point estimates were compared to those obtained using Cox regression on the full cohort. Computational efficiencies were evaluated by comparing central processing unit times required for analysis of the cohort at sizes 1, 2, 4, 8, 16, and 32 times its initial size.ResultsNested case-control analyses yielded results that were similar to results of Cox regression on the full cohort. Cox regression was found to be 125 times slower than the nested case-control approach (using four controls per case).ConclusionsThe nested case-control approach is a useful alternative for cohort analysis when studying time-dependent exposures. Its superior computational efficiency may be particularly useful when studying rare outcomes in databases, where the ability to analyze larger sample sizes can improve the power of the study.

Time-Dependent Hazard Ratio: Modeling and Hypothesis Testing with Application in Lupus Nephritis

Abstract We investigate the association between duration of untreated disease and survival in lupus nephritis, a rare rheumatologic disease. In this case, as in many other studies of survival, a priori considerations suggest that the effect of the predictor on hazard may change with increasing follow-up time. To accommodate such situations, we use regression splines to model the hazard ratio as a flexible function of time. We propose model-based tests of the hypotheses of hazards proportionality and of no association. We evaluate the accuracy of estimation and inference in simulations and also present analysis of a larger medical data set.