A case study of an individual participant data meta-analysis of diagnostic accuracy showed that prediction regions represented heterogeneity well

The diagnostic accuracy of a screening tool is often characterized by its sensitivity and specificity. An analysis of these measures must consider their intrinsic correlation. In the context of an individual participant data meta-analysis, heterogeneity is one of the main components of the analysis. When using a random-effects meta-analytic model, prediction regions provide deeper insight into the effect of heterogeneity on the variability of estimated accuracy measures across the entire studied population, not just the average. This study aimed to investigate heterogeneity via prediction regions in an individual participant data meta-analysis of the sensitivity and specificity of the Patient Health Questionnaire-9 for screening to detect major depression. From the total number of studies in the pool, four dates were selected containing roughly 25%, 50%, 75% and 100% of the total number of participants. A bivariate random-effects model was fitted to studies up to and including each of these dates to jointly estimate sensitivity and specificity. Two-dimensional prediction regions were plotted in ROC-space. Subgroup analyses were carried out on sex and age, regardless of the date of the study. The dataset comprised 17,436 participants from 58 primary studies of which 2322 (13.3%) presented cases of major depression. Point estimates of sensitivity and specificity did not differ importantly as more studies were added to the model. However, correlation of the measures increased. As expected, standard errors of the logit pooled TPR and FPR consistently decreased as more studies were used, while standard deviations of the random-effects did not decrease monotonically. Subgroup analysis by sex did not reveal important contributions for observed heterogeneity; however, the shape of the prediction regions differed. Subgroup analysis by age did not reveal meaningful contributions to the heterogeneity and the prediction regions were similar in shape. Prediction intervals and regions reveal previously unseen trends in a dataset. In the context of a meta-analysis of diagnostic test accuracy, prediction regions can display the range of accuracy measures in different populations and settings

Effect of current and lifetime posttraumatic stress disorder on 24-h urinary catecholamines and cortisol: results from the Mind Your Heart Study

Posttraumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular disease and several other chronic illnesses. Alterations in the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis in PTSD might contribute to these associations but findings regarding SNS and HPA activity in PTSD are heterogeneous. We measured 24-h urinary catecholamines and cortisol in a large cohort of adult outpatients recruited from 2 Veterans Affairs medical centers. 24-h urinary norepinephrine, epinephrine, dopamine and cortisol were measured by tandem mass spectrometry. Lifetime and current PTSD were assessed with the Clinician Administered PTSD Scale using DSM-IV-TR criteria. Out of 613 participants, 199 (32.5%) had current PTSD, 100 (16.3%) had lifetime but not current PTSD, and 314 (51.2%) never had PTSD. Patients with current PTSD had significantly higher norepinephrine secretion compared to those without PTSD. Patients in the lifetime PTSD group exhibited lower cortisol values compared to those without PTSD. Participants who never had PTSD showed the lowest norepinephrine and the highest cortisol values. All results remained stable when controlling for potentially confounding variables. This study provides evidence for increased norepinephrine secretion and decreased cortisol in PTSD. Future longitudinal studies are needed to determine whether these changes contribute to adverse health outcomes in patients with PTSD

Antidepressants, autonomic function and mortality in patients with coronary heart disease: data from the Heart and Soul Study

Background: Antidepressants reduce depressive symptoms in patients with coronary heart disease, but they may be associated with increased mortality. This study aimed to examine whether the use of tricyclic antidepressants (TCA) or selective serotonin reuptake inhibitors (SSRI) is associated with mortality in patients with coronary heart disease, and to determine whether this association is mediated by autonomic function. Method: A total of 956 patients with coronary heart disease were followed for a mean duration of 7.2 years. Autonomic function was assessed as heart rate variability, and plasma and 24-h urinary norepinephrine. Results: Of 956 patients, 44 (4.6%) used TCA, 89 (9.3%) used SSRI, and 823 (86.1%) did not use antidepressants. At baseline, TCA users exhibited lower heart rate variability and higher norepinephrine levels compared with SSRI users and antidepressant non-users. At the end of the observational period, 52.3% of the TCA users had died compared with 38.2% in the SSRI group and 37.3% in the control group. The adjusted hazard ratio (HR) for TCA use compared with non-use was 1.74 [95% confidence interval (CI) 1.12-2.69, p = 0.01]. Further adjustment for measures of autonomic function reduced the association between TCA use and mortality (HR = 1.27, 95% CI 0.67-2.43, p = 0.47). SSRI use was not associated with mortality (HR = 1.15, 95% CI 0.81-1.64, p = 0.44). Conclusions: The use of TCA was associated with increased mortality. This association was at least partially mediated by differences in autonomic function. Our findings suggest that TCA should be avoided in patients with coronary heart disease

Scared to death? Generalized anxiety disorder and cardiovascular events in patients with stable coronary heart disease the Heart and Soul Study

Context: Anxiety is common in patients with coronary heart disease (CHD), but studies examining the effect of anxiety on cardiovascular prognosis and the role of potential mediators have yielded inconsistent results. Objectives: To evaluate the effect of generalized anxiety disorder (GAD) on subsequent cardiovascular events and the extent to which this association is explained by cardiac disease severity and potential behavioral or biological mediators. Design: Prospective cohort study (Heart and Soul Study). Setting: Participants were recruited between September 11, 2000, and December 20, 2002, from 12 outpatient clinics in the San Francisco Bay Area and were followed up until March 18, 2009. Participants: One thousand fifteen outpatients with stable CHD followed up for a mean (SD) of 5.6 (1.8) years. Main Outcome Measures: We determined the presence of GAD using the Diagnostic Interview Schedule. Proportional hazards models were used to evaluate the association of GAD with subsequent cardiovascular events and the extent to which this association was explained by potential confounders and mediators. Results: A total of 371 cardiovascular events occurred during 5711 person-years of follow-up. The age-adjusted annual rate of cardiovascular events was 9.6% in the 106 participants with GAD and 6.6% in the 909 participants without GAD (P = .03). After adjustment for demographic characteristics, comorbid conditions ( including major depressive disorder), cardiac disease severity, and medication use, GAD remained associated with a 62% higher rate of cardiovascular events ( hazard ratio, 1.62; 95% confidence interval, 1.11-2.37; P = .01). Additional adjustment for a variety of potential behavioral and biological mediators had little effect on this association ( hazard ratio, 1.74; 95% confidence interval, 1.13-2.67; P = .01). Conclusions: In outpatients with CHD, a robust association between GAD and cardiovascular events was found that could not be explained by disease severity, health behaviors, or biological mediators. How GAD leads to poor cardiovascular outcomes deserves further study

Differential associations between specific depressive symptoms and cardiovascular prognosis in patients with stable coronary heart disease

Objectives The purpose of this research was to evaluate the relationship between cognitive and somatic depressive symptoms and cardiovascular prognosis. Background Depression in patients with stable coronary heart disease (CHD) is associated with poor cardiac prognosis. Whether certain depressive symptoms are more cardiotoxic than others is unknown. Methods In the Heart and Soul Study, 1,019 patients with stable CHD were assessed using the Patient Health Questionnaire to determine the presence of the 9 depressive symptoms included in the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. The mean age of the patients was 67 years, and 82% were men. A comparison was made on a new cardiovascular event (myocardial infarction, stroke, transient ischemic attack, or congestive heart failure) or death (mean follow-up duration 6.1 +/- 2.0 years) on the basis of cognitive and somatic sum scores and for patients with or without each of those specific depressive symptoms. Demographic characteristics, cardiac risk factors, and cardiac medications were controlled for. Results After adjustment for demographic data and cardiac risk factors, each somatic symptom was associated with 14% greater risk for events (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.05 to 1.24; p = 0.002). Fatigue (HR: 1.34; 95% CI: 1.07 to 1.67; p = 0.01), appetite problems (HR: 1.46; 95% CI: 1.12 to 1.91; p = 0.005), and sleeping difficulties (HR: 1.26; 95% CI: 1.00 to 1.58; p = 0.05) were most strongly predictive of cardiovascular events. In contrast, cognitive symptoms (HR: 1.08; 95% CI: 0.99 to 1.17; p = 0.09) were not significantly associated with cardiovascular events. Conclusions In patients with stable CHD, somatic symptoms of depression were more strongly predictive of cardiovascular events than cognitive symptoms, although the CIs surrounding these estimates had substantial overlap. These findings are highly consistent with those of previous studies. Further research is needed to understand the pathophysiological processes by which somatic depressive symptoms contribute to prognosis in patients with CHD. (J Am Coll Cardiol 2010;56:838-44) (C) 2010 by the American College of Cardiology Foundation