Sex and race differences of cerebrospinal fluid metabolites in healthy individuals.

INTRODUCTION: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown. OBJECTIVE: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). METHODS: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015). RESULTS: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences. CONCLUSION: Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

The role of comorbid anxiety in exercise and depression trials: Secondary analysis of the SMILE-II randomized clinical trial.

OBJECTIVES: To explore the anxiolytic effects of a 4-month randomized, placebo-controlled trial of exercise and antidepressant medication in patients with major depressive disorder (MDD), and to examine the potential modifying effects of anxiety in treating depressive symptoms. MATERIALS AND METHODS: In this secondary analysis of the SMILE-II trial, 148 sedentary adults with MDD were randomized to: (a) supervised exercise, (b) home-based exercise, (c) sertraline, or (d) placebo control. Symptoms of state anxiety measured by the Spielberger Anxiety Inventory were examined before and after 4 months of treatment. Depressive symptoms were assessed by the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory-II (BDI-II). Analyses were carried out using general linear models. RESULTS: Compared to placebo controls, the exercise and sertraline groups had lower state anxiety scores (standardized difference = 0.3 [95% CI = -0.6, -0.04]; p = 0.02) after treatment. Higher pretreatment state anxiety was associated with poorer depression outcomes in the active treatments compared to placebo controls for both the HAMD (p = .004) and BDI-II (p = .02). CONCLUSION: Aerobic exercise as well as sertraline reduced symptoms of state anxiety in patients with MDD. Higher levels of pretreatment anxiety attenuated the effects of the interventions on depressive symptoms, however, especially among exercisers. Patients with MDD with higher comorbid state anxiety appear to be less likely to benefit from exercise interventions in reducing depression and thus may require supplemental treatment with special attention to anxiety.

Time of Day When Type 1 Diabetes Patients With Eating Disorder Symptoms Most Commonly Restrict Insulin.

OBJECTIVE: Restricting insulin to lose weight is a significant problem in the clinical management of type 1 diabetes (T1D). Little is known about this behavior or how to effectively intervene. Identifying when insulin restriction occurs could allow clinicians to target typical high-risk times or formulate hypotheses regarding factors that influence this behavior. The current study investigated the frequency of insulin restriction by time of day. METHODS: Fifty-nine adults with T1D and eating disorder symptoms completed 72 hours of real-time reporting of eating and insulin dosing with continuous glucose monitoring. We used a generalized estimating equation model to test the global hypothesis that frequency of insulin restriction (defined as not taking enough insulin to cover food consumed) varied by time of day, and examined frequency of insulin restriction by hour. We also examined whether patterns of insulin restriction for 72 hours corresponded with patients' interview reports of insulin restriction for the past 28 days. RESULTS: Frequency of insulin restriction varied as a function of time (p = .016). Insulin restriction was the least likely in the morning hours (6:00-8:59 AM), averaging 6% of the meals/snacks consumed. Insulin restriction was more common in the late afternoon (3:00-5:59 PM), peaking at 29%. Insulin was restricted for 32% of the meals/snacks eaten overnight (excluding for hypoglycemia); however, overnight eating was rare. Insulin restriction was associated with higher 120-minute postprandial blood glucose (difference = 44.4 mg/dL, 95% confidence interval = 22.7-68.5, p < .001) and overall poorer metabolic control (r = 0.43-0.62, p's < .01). Patients reported restricting insulin for a greater percentage of meals and snacks for the past 28 days than during the 72 hour real-time assessment; however, the reports were correlated (Spearman's ρ = 0.46, p < .001) and accounted for similar variance in HbA1c (34% versus 35%, respectively). CONCLUSIONS: Findings suggest that insulin restriction may be less likely in the morning, and that late afternoon is a potentially important time for additional therapeutic support. Results also suggest that systematic clinical assessment and treatment of overnight eating might improve T1D management.

Brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism is associated with disease severity and incidence of cardiovascular events in a patient cohort.

BACKGROUND: The rs6265 (Val66Met) single-nucleotide polymorphism in the BDNF gene has been related to a number of endophenotypes that have in turn been shown to confer risk for atherosclerotic cardiovascular disease (CVD). To date, however, very few studies have examined the association of the Val66Met single-nucleotide polymorphism with CVD clinical outcomes. METHODS: In a cohort of 5,510 Caucasian patients enrolled in the CATHeterization GENetics (CATHGEN) study at Duke University Hospital between 2001 and 2011, we determined the severity of coronary artery disease (CAD) and CVD event incidence through up to 11.8years of follow-up. We examined the association of Val66Met genotype with time-to-death or myocardial infarction, adjusting for age, sex, CAD risk variables, and CAD severity measures. RESULTS: The Val/Val genotype was associated with a higher risk than Met carriers for clinical CVD events (P=.034, hazard ratio 1.12, 95% CI 1.01-1.24). In addition, compared with Met carriers, individuals with the Val/Val genotype had a greater odds of having more diseased vessels (odds ratio 1.17, 95% CI 1.06-1.30, P=.002), and lower left ventricular ejection fraction (ß=-0.72, 95% CI, -1.42 to -0.02, P=.044). CONCLUSIONS: The Val/Val genotype was associated with greater severity of CAD and incidence of CVD-related clinical events in a patient sample. If these findings are confirmed in further research, intervention studies in clinical groups with the Val/Val genotype could be undertaken to prevent disease and improve prognosis.

Population differences in associations of serotonin transporter promoter polymorphism (5HTTLPR) di- and triallelic genotypes with blood pressure and hypertension prevalence.

Based on prior research finding the 5HTTLPR L allele associated with increased cardiovascular reactivity to laboratory stressors and increased risk of myocardial infarction, we hypothesized that the 5HTTLPR L allele will be associated with increased blood pressure (BP) and increased hypertension prevalence in 2 large nationally representative samples in the United States and Singapore. METHODS: Logistic regression and linear models tested associations between triallelic (L'S', based on rs25531) 5HTTLPR genotypes and hypertension severity and mean systolic and diastolic blood pressure (SBP and DBP) collected during the Wave IV survey of the National Longitudinal Study of Adolescent to Adult Health (Add Health, N=11,815) in 2008-09 and during 2004-07 in 4196 Singaporeans. RESULTS: In US Whites, L' allele carriers had higher SBP (0.9 mm Hg, 95% CI=0.26-1.56) and greater odds (OR=1.23, 95% CI=1.10-1.38) of more severe hypertension than those with S'S' genotypes. In African Americans, L' carriers had lower mean SBP (-1.27mm Hg, 95% CI=-2.53 to -0.01) and lower odds (OR = 0.78, 95% CI=0.65-0.94) of more severe hypertension than those with the S'S' genotype. In African Americans, those with L'L' genotypes had lower DBP (-1.13mm Hg, 95% CI=-2.09 to -0.16) than S' carriers. In Native Americans, L' carriers had lower SBP (-6.05mm Hg, 95% CI=-9.59 to -2.51) and lower odds of hypertension (OR = 0.34, 95% CI=0.13-0.89) than those with the S'S' genotype. In Asian/Pacific Islanders those carrying the L' allele had lower DBP (-1.77mm Hg, 95% CI=-3.16 to -0.38) and lower odds of hypertension (OR = 0.68, 95% CI=0.48-0.96) than those with S'S'. In the Singapore sample S' carriers had higher SBP (3.02mm Hg, 95% CI=0.54-5.51) and DBP (1.90mm Hg, 95% CI=0.49-3.31) than those with the L'L' genotype. CONCLUSIONS: These findings suggest that Whites carrying the L' allele, African Americans and Native Americans with the S'S' genotype, and Asians carrying the S' allele will be found to be at higher risk of developing cardiovascular disease and may benefit from preventive measures.

Computing a Synthetic Chronic Psychosocial Stress Measurement in Multiple Datasets and its Application in the Replication of G × E Interactions of the EBF1 Gene.

Chronic psychosocial stress adversely affects health and is associated with the development of disease [Williams, 2008]. Systematic epidemiological and genetic studies are needed to uncover genetic variants that interact with stress to modify metabolic responses across the life cycle that are the proximal contributors to the development of cardiovascular disease and precipitation of acute clinical events. Among the central challenges in the field are to perform and replicate gene-by-environment (G × E) studies. The challenge of measurement of individual experience of psychosocial stress is magnified in this context. Although many research datasets exist that contain genotyping and disease-related data, measures of psychosocial stress are often either absent or vary substantially across studies. In this paper, we provide an algorithm to create a synthetic measure of chronic psychosocial stress across multiple datasets, applying a consistent criterion that uses proxy indicators of stress components. We validated the computed scores of chronic psychosocial stress by observing moderately strong and significant correlations with the self-rated chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis Cohort (Rho = 0.23, P < 0.0001) and with the measures of depressive symptoms in five datasets (Rho = 0.15-0.42, Ps = 0.005 to <0.0001) and by comparing the distributions of the self-rated and computed measures. Finally, we demonstrate the utility of this computed chronic psychosocial stress variable by providing three additional replications of our previous finding of gene-by-stress interaction with central obesity traits [Singh et al., 2015].

Treatment of anxiety in patients with coronary heart disease: Rationale and design of the UNderstanding the benefits of exercise and escitalopram in anxious patients WIth coroNary heart Disease (UNWIND) randomized clinical trial.

BACKGROUND: Anxiety is highly prevalent among patients with coronary heart disease (CHD), and there is growing evidence that high levels of anxiety are associated with worse prognosis. However, few studies have evaluated the efficacy of treating anxiety in CHD patients for reducing symptoms and improving clinical outcomes. Exercise and selective serotonin reuptake inhibitors have been shown to be effective in treating patients with depression, but have not been studied in cardiac patients with high anxiety. METHODS: The UNWIND trial is a randomized clinical trial of patients with CHD who are at increased risk for adverse events because of comorbid anxiety. One hundred fifty participants with CHD and elevated anxiety symptoms and/or with a diagnosed anxiety disorder will be randomly assigned to 12 weeks of aerobic exercise (3×/wk, 35 min, 70%-85% VO2peak), escitalopram (5-20 mg qd), or placebo. Before and after 12 weeks of treatment, participants will undergo assessments of anxiety symptoms and CHD biomarkers of risk, including measures of inflammation, lipids, hemoglobin A1c, heart rate variability, and vascular endothelial function. Primary outcomes include post-intervention effects on symptoms of anxiety and CHD biomarkers. Secondary outcomes include clinical outcomes (cardiovascular hospitalizations and all-cause death) and measures of quality of life. CONCLUSIONS: The UNWIND trial (ClinicalTrials.gov NCT02516332) will evaluate the efficacy of aerobic exercise and escitalopram for improving anxiety symptoms and reducing risk for adverse clinical events in anxious CHD patients.

The effects of a telehealth coping skills intervention on outcomes in chronic obstructive pulmonary disease: primary results from the INSPIRE-II study.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality and reduced quality of life (QoL). Novel interventions are needed to improve outcomes in COPD patients. The present study assessed the effects of a telephone-based coping skills intervention on psychological and somatic QoL and on the combined medical end point of COPD-related hospitalizations and all-cause mortality. METHODS: We conducted a dual-site, randomized clinical trial with assessments at baseline and after 16 weeks of treatment. The study population comprised 326 outpatients with COPD aged 38 to 81 years, randomized to coping skills training (CST) or to COPD education (COPD-ED). Patients completed a battery of QoL instruments, pulmonary function tests, and functional measures and were followed up for up to 4.4 years to assess medical outcomes. RESULTS: The CST group exhibited greater improvements in psychological QoL compared with controls (p = .001), including less depression (Cohen d = 0.22 [95% confidence interval, or CI = 0.08-0.36]) and anxiety (d = 0.17 [95% CI = 0.02-0.33]), and better overall mental health (d = 0.17 [95% CI = 0.03-0.32]), emotional role functioning (d = 0.29 [95% CI = 0.10-0.48]), vitality (d = 0.27 [95% CI = 0.11, 0.42]), and social functioning (d = 0.21 [95% CI = 0.03-0.38]). A significant baseline psychological QoL by treatment group interaction revealed that CST with lower QoL at baseline achieved even greater improvements in psychological QoL compared with COPD-ED. CST participants also exhibited greater improvements in somatic QoL (p = .042), including greater improvements in pulmonary QoL (d = 0.13 [95% CI = 0.01-0.24]), less fatigue (d = 0.34 [95% CI = 0.18-0.50]), and less shortness of breath (d = 0.11 [95% CI = -0.01 to 0.23]) and greater improvement in distance walked on the Six-Minute Walk test (d = 0.09 [95% CI = 0.01-0.16]). However, there was no significant difference in risk of time to COPD-related hospitalization or all-cause mortality between CST (34 events) and COPD-ED (32 events; p = 0.430). CONCLUSIONS: A telehealth CST intervention produced clinically meaningful improvements in QoL and functional capacity, but no overall improvement in risk of COPD-related hospitalization and all-cause mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00736268.

Socioeconomic indices as independent correlates of C-reactive protein in the National Longitudinal Study of Adolescent Health.

OBJECTIVES: To examine the association between socioeconomic status (SES) and C-reactive protein (CRP) to understand how SES may increase the risk of cardiovascular disease and thus identify targets for prevention measures. METHODS: Path models were used to examine direct and indirect associations of four indices of SES (objective early life built environment ratings, parental and participant education, and income) with CRP measured during early adulthood using data from the National Longitudinal Adolescent Health Study (n = 11,371; mean age = 29 years, range = 24-32 years; 53.8% women, 28.0% black participants). The present study examined potential mediation of the association of SES with CRP by way of body mass index (BMI), smoking, and alcohol consumption within white and black men and women. RESULTS: BMI was a mediator of the relation between parent education and CRP for white men (path coefficient [γ] = -0.05, p < .001) and women (γ = -0.05, p < .001). Smoking mediated the income-CRP (γ = -0.01, p < .01) and the education-CRP (γ = -0.07, p < .001) relation for white men. BMI mediated the relation between all measures of SES and CRP for white women (γ values between -0.02 and -0.05; p values < .01). None of the risk factors mediated the SES-CRP relation in black participants. CONCLUSIONS: These findings indicate that the association of SES with CRP is influenced by both the timing and type of SES measure examined. In addition, race and sex play a role in how potential mediators are involved with the SES-CRP relationship, such that BMI and smoking were mediators in white men, whereas BMI was the sole mediator in white women.

Stress and coping in caregivers of patients awaiting solid organ transplantation.

Caregivers for patients undergoing solid organ transplantation play an essential role in the process of transplantation. However, little is known about stress and coping among these caregivers. Six hundred and twenty-one primary caregivers of potential candidates for lung (n = 317), liver (n = 147), heart (n = 115), and/or kidney (n = 42) transplantation completed a psychometric test battery at the time of the candidate's initial pre-transplant psychosocial evaluation. Caregivers were generally well adjusted, with only 17% exhibiting clinical symptoms of depression (Beck Depression Inventory-II score >13) and 13% reporting clinical levels of anxiety (State Trait Anxiety Inventory score >48). Greater caregiver burden and negative coping styles were associated with higher levels of depression. Greater objective burden and avoidant coping were associated with higher levels of anxiety. Caregivers evidenced a high degree of socially desirable (i.e., defensive) responding, which may reflect a deliberate effort to minimize fears or worries so as to not jeopardize patients' listing status.

Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial.

CONTEXT: Depression is common in patients with cardiac disease, especially in patients with heart failure, and is associated with increased risk of adverse health outcomes. Some evidence suggests that aerobic exercise may reduce depressive symptoms, but to our knowledge the effects of exercise on depression in patients with heart failure have not been evaluated. OBJECTIVE: To determine whether exercise training will result in greater improvements in depressive symptoms compared with usual care among patients with heart failure. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized controlled trial involving 2322 stable patients treated for heart failure at 82 medical clinical centers in the United States, Canada, and France. Patients who had a left ventricular ejection fraction of 35% or lower, had New York Heart Association class I to IV heart failure, and had completed the Beck Depression Inventory II (BDI-II) score were randomized (1:1) between April 2003 and February 2007. Depressive scores ranged from 0 to 59; scores of 14 or higher are considered clinically significant. INTERVENTIONS: Participants were randomized either to supervised aerobic exercise (goal of 90 min/wk for months 1-3 followed by home exercise with a goal of ≥120 min/wk for months 4-12) or to education and usual guideline-based heart failure care. MAIN OUTCOME MEASURES: Composite of death or hospitalization due to any cause and scores on the BDI-II at months 3 and 12. RESULTS: Over a median follow-up period of 30 months, 789 patients (68%) died or were hospitalized in the usual care group compared with 759 (66%) in the aerobic exercise group (hazard ratio [HR], 0.89; 95% CI, 0.81 to 0.99; P = .03). The median BDI-II score at study entry was 8, with 28% of the sample having BDI-II scores of 14 or higher. Compared with usual care, aerobic exercise resulted in lower mean BDI-II scores at 3 months (aerobic exercise, 8.95; 95% CI, 8.61 to 9.29 vs usual care, 9.70; 95% CI, 9.34 to 10.06; difference, -0.76; 95% CI,-1.22 to -0.29; P = .002) and at 12 months (aerobic exercise, 8.86; 95% CI, 8.67 to 9.24 vs usual care, 9.54; 95% CI, 9.15 to 9.92; difference, -0.68; 95% CI, -1.20 to -0.16; P = .01). CONCLUSIONS: Compared with guideline-based usual care, exercise training resulted in a modest reduction in depressive symptoms, although the clinical significance of this improvement is unknown. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00047437.

Coping effectively with heart failure (COPE-HF): design and rationale of a telephone-based coping skills intervention.

BACKGROUND: Coping Effectively with Heart Failure (COPE-HF) is an ongoing randomized clinical trial funded by the National Institutes of Health to evaluate if a coping skills training (CST) intervention will result in improved health status and quality of life as well as reduced mortality and hospitalizations compared with a heart failure education (HFE) intervention. METHODS AND RESULTS: Two hundred heart failure (HF) patients recruited from the Duke University Medical Center and the University of North Carolina Hospital system will be randomized to a CST intervention (16 weekly 30-minute telephone counseling sessions including motivational interviewing and individually tailored cognitive behavioral therapy) or to an HFE intervention (16 weekly 30-minute telephone sessions including education and symptom monitoring). Primary outcomes will include postintervention effects on HF biomarkers (B-type natriuretic peptide, ejection fraction) and quality of life, as well as long-term clinical outcomes (hospitalizations and death). Secondary analyses will include an evaluation of treatment effects across subpopulations, and potential mechanisms by which CST may improve clinical outcomes. CONCLUSIONS: COPE-HF is a proof-of-concept study that should provide important insights into the health benefits of a CST intervention designed to enhance HF self-management, improve health behaviors, and reduce psychologic distress.

Exercise and pharmacotherapy in patients with major depression: one-year follow-up of the SMILE study.

OBJECTIVE: To examine a 1-year follow-up of a 4-month, controlled clinical trial of exercise and antidepressant medication in patients with major depressive disorder (MDD). METHODS: In the original study, 202 sedentary adults with MDD were randomized to: a) supervised exercise; b) home-based exercise; c) sertraline; or d) placebo pill. We examined two outcomes measured at 1-year follow-up (i.e., 16 months post randomization): 1) continuous Hamilton Depression Rating Scale score; and 2) MDD status (depressed; partial remission; full remission) in 172 available participants (85% of the original cohort). Regression analyses were performed to examine the effects of treatment group assignment, as well as follow-up antidepressant medication use and self-reported exercise (Godin Leisure-Time Exercise Questionnaire), on the two outcomes. RESULTS: In the original study, patients receiving exercise achieved similar benefits compared with those receiving sertraline. At the time of the 1-year follow-up, rates of MDD remission increased from 46% at post treatment to 66% for participants available for follow-up. Neither initial treatment group assignment nor antidepressant medication use during the follow-up period were significant predictors of MDD remission at 1 year. However, regular exercise during the follow-up period predicted both Hamilton Depression Rating Scale scores and MDD diagnosis at 1 year. This relationship was curvilinear, with the association concentrated between 0 minute and 180 minutes of weekly exercise. CONCLUSION: The effects of aerobic exercise on MDD remission seem to be similar to sertraline after 4 months of treatment; exercise during the follow-up period seems to extend the short-term benefits of exercise and may augment the benefits of antidepressant use. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00331305.

The DASH diet and insulin sensitivity.

Lifestyle modifications, including adoption of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, weight loss in individuals who are overweight or obese, and physical activity, are effective in the prevention and treatment of hypertension. A healthy lifestyle may also have beneficial effects on metabolic abnormalities, such as insulin resistance, that are associated with high blood pressure. This review examines the independent and combined effects of the DASH diet and weight loss plus exercise on blood pressure and insulin sensitivity, with a focus on recently published results from the ENCORE study. Our data suggest that the DASH eating plan alone lowers blood pressure in overweight individuals with higher than optimal blood pressure, but significant improvements in insulin sensitivity are observed only when the DASH diet is implemented as part of a more comprehensive lifestyle modification program that includes exercise and weight loss.

Exercise Prescription Practices to Improve Mental Health.

OBJECTIVE: There is growing evidence that higher levels of physical activity are associated with better mental health. Furthermore, interventional studies have shown that exercise may improve symptoms in a number of psychiatric conditions. Despite this evidence, relatively little information is available about how these findings have been translated into clinical practice. The goal of this study was to characterize the exercise prescribing practices of health care providers from different subspecialties and evaluate factors that may influence their prescribing practices. METHODS: We conducted a cross-sectional survey among faculty and staff from a large academic tertiary care medical center in the southeastern United States. Participants were invited to complete the survey via email or departmental newsletters. Descriptive statistics were used to characterize the sample and ordered logistic regression was used to analyze practices about exercise as a therapy for psychiatric illness. RESULTS: A total of 185 respondents completed the survey. More than half of the providers (58%) reported that they regularly recommend exercise as part of the treatment for patients with psychiatric conditions; however, few providers offered specific exercise instructions (24%) or followed national guidelines (30%). Depression (84.9%) and anxiety (69.2%) were the most common indications for exercise prescription, while insufficient knowledge or training was the most common barrier to prescribing exercise. We also found significant differences in prescription practices depending on the providers' formal clinical degree and their reported personal exercise habits. CONCLUSIONS: Exercise is recognized by most clinicians as a therapeutic option for psychiatric conditions. Despite this recognition, only a small proportion provide recommendations consistent with national guidelines or empirical research.

Confirmatory factor analysis: an introduction for psychosomatic medicine researchers.

We present an introduction to the basic concepts essential to understanding confirmatory factor analysis (CFA). We initially discuss the underlying mathematical model and its graphical representation. We then show how parameters are estimated for the CFA model based on the maximum likelihood function. Finally, we discuss several ways in which model fit is evaluated as well as introduce the concept of model identification. In our presentation, we use an example to illustrate the application of CFA to psychosomatic research and touch on the more general role of structural equation modeling in psychosomatic research.

Phobic anxiety and increased risk of mortality in coronary heart disease.

OBJECTIVES: To evaluate whether phobic anxiety is associated with increased risk of cardiac mortality in individuals with established coronary heart disease (CHD) and to examine the role of reduced heart rate variability (HRV) in mediating this risk. Previous findings suggest that phobic anxiety may pose increased risk of cardiac mortality in medically healthy cohorts. METHODS: We performed a prospective cohort study in 947 CHD patients recruited during hospitalization for coronary angiography. At baseline, supine recordings of heart rate for HRV were collected, and participants completed the Crown-Crisp phobic anxiety scale. Fatal cardiac events were identified over an average period of 3 years. RESULTS: Female CHD patients reported significantly elevated levels of phobic anxiety when compared with male patients (p < .001), and survival analysis showed an interaction between gender and phobic anxiety in the prediction of cardiac mortality (p = .058) and sudden cardiac death (p = .03). In women, phobic anxiety was associated with a 1.6-fold increased risk of cardiac mortality (hazard ratio, 1.56; 95% confidence interval, 1.15-2.11; p = .004) and a 2.0-fold increased risk of sudden cardiac death (hazard ratio, 2.02; 95% confidence interval, 1.16-3.52; p = .01) and was unassociated with increased mortality risk in men (p = .56). Phobic anxiety was weakly associated with reduced high-frequency HRV in female patients (r = -.14, p = .02), but reduced HRV did not alter the association between phobic anxiety on mortality. CONCLUSIONS: Phobic anxiety levels are high in women with CHD and may be a risk factor for cardiac-related mortality in women diagnosed with CHD. Reduced HRV measured during rest does not seem to mediate phobic anxiety-related risk.

Cerebrovascular risk factors and cerebral hyperintensities among middle-aged and older adults with major depression.

OBJECTIVES: To examine the association between cerebral hyperintensities and cerebrovascular risk factors (CVRF) among middle-aged and older adults with major depressive disorder (MDD). METHODS: Thirty patients (aged 55-77 years) with MDD and no history of stroke participated in a magnetic resonance imaging assessment to assess for the presence of cerebral hyperintensities and underwent a physical examination to assess stroke risk as indexed by the Framingham Stroke Risk Profile (FSRP). In addition, intima medial thickness (IMT) was measured in the left and right carotid arteries. RESULTS: Higher FSRP levels were associated with total greater cerebral hyperintensities (r = 0.64), as well as greater subependymal hyperintensities (r = 0.47), confluent periventricular changes (r = 0.46), and tended to be associated with subcortical gray matter hyperintensities (r = 0.34). A quadratic relationship was observed between IMT and total cerebral hyperintensities (b = 4.84), and higher IMT levels were associated with greater subependymal hyperintensities (r = 0.40). CONCLUSIONS: Higher levels of CVRF are associated with graded increases in cerebral hyperintensities among middle-aged and older adults with MDD.

Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants.

In prior work, we identified a novel gene-by-stress association of EBF1's common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to "racism/discrimination" (P = 0.036) and "not meeting basic needs" (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e-03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.