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1.  Longitudinal Changes in Depression Symptoms and Survival Among Patients With Lung Cancer: A National Cohort Assessment 
Journal of Clinical Oncology  2016;34(33):3984-3991.
Depression symptoms are common among patients with lung cancer; however, longitudinal changes and their impact on survival are understudied.
This was a prospective, observational study from the Cancer Care Outcomes Research and Surveillance Consortium from five US geographically defined regions from September 2003 through December 2005. Patients enrolled within 3 months of their lung cancer diagnosis were eligible. The eight-item Center for Epidemiologic Studies Depression scale was administered at diagnosis and 12 months’ follow-up. The main outcome was survival, which was evaluated using Kaplan-Meyer curves and adjusted Cox proportional hazards modeling.
Among 1,790 participants, 681 (38%) had depression symptoms at baseline and an additional 105 (14%) developed new-onset depression symptoms during treatment. At baseline, depression symptoms were associated with increased mortality (hazard ratio [HR], 1.17; 95% CI, 1.03 to 1.32; P = .01). Participants were classified into the following four groups based on longitudinal changes in depression symptoms from baseline to follow-up: never depression symptoms (n = 640), new-onset depression symptoms (n = 105), depression symptom remission (n = 156), and persistent depression symptoms (n = 254) and HRs were calculated. Using the never-depression symptoms group as a reference group, HRs were as follows: new-onset depression symptoms, 1.50 (95% CI, 1.12 to 2.01; P = .006); depression symptom remission, 1.02 (95% CI, 0.79 to 1.31; P = .89), and persistent depression symptoms, 1.42 (95% CI, 1.15 to 1.75; P = .001). At baseline, depression symptoms were associated with increased mortality among participants with early-stage disease (stages I and II; HR, 1.61; 95% CI, 1.26 to 2.04), but not late-stage disease (stages III and IV; HR, 1.05; 95% CI, 0.91 to 1.22). At follow-up, depression symptoms were associated with increased mortality among participants with early-stage disease (HR, 1.71; 95% CI, 1.27 to 2.31) and those with late-stage disease (HR, 1.32; 95% CI, 1.04 to 1.69).
Among patients with lung cancer, longitudinal changes in depression symptoms are associated with differences in mortality, particularly among patients with early-stage disease. Symptom remission is associated with a similar mortality rate as never having had depression.
PMCID: PMC5477833  PMID: 27996350
2.  Correlates of Suicide Among Veterans Treated in Primary Care: Case–Control Study of a Nationally Representative Sample 
Journal of General Internal Medicine  2014;29(Suppl 4):853-860.
Veterans receiving Veterans Affairs (VA) healthcare have increased suicide risk compared to the general population. Many patients see primary care clinicians prior to suicide. Yet little is known about the correlates of suicide among patients who receive primary care treatment prior to death.
Our aim was to describe characteristics of veterans who received VA primary care in the 6 months prior to suicide; and to compare these to characteristics of control patients who also received VA primary care.
This was a retrospective case–control study.
The investigators partnered with VA operations leaders to obtain death certificate data from 11 states for veterans who died by suicide in 2009. Cases were matched 1:2 to controls based on age, sex, and clinician.
Demographic, diagnosis, and utilization data were obtained from VA’s Corporate Data Warehouse. Additional clinical and psychosocial context data were collected using manual medical record review. Multivariate conditional logistic regression was used to examine associations between potential predictor variables and suicide.
Two hundred and sixty-nine veteran cases were matched to 538 controls. Average subject age was 63 years; 97 % were male. Rates of mental health conditions, functional decline, sleep disturbance, suicidal ideation, and psychosocial stressors were all significantly greater in cases compared to controls. In the final model describing men in the sample, non-white race (OR = 0.51; 95 % CI = 0.27–0.98) and VA service-connected disability (OR = 0.54; 95 % CI = 0.36–0.80) were associated with decreased odds of suicide, while anxiety disorder (OR = 3.52; 95 % CI = 1.79–6.92), functional decline (OR = 2.52; 95 % CI = 1.55–4.10), depression (OR = 1.82; 95 % CI = 1.07–3.10), and endorsement of suicidal ideation (OR = 2.27; 95 % CI = 1.07–4.83) were associated with greater odds of suicide.
Assessment for anxiety disorders and functional decline in addition to suicidal ideation and depression may be especially important for determining suicide risk in this population. Continued development of interventions that support identifying and addressing these conditions in primary care is indicated.
PMCID: PMC4239287  PMID: 25355088
mental health; veterans; primary care; health services research
3.  Posttraumatic Stress Disorder and Incidence of Type-2 Diabetes: A Prospective Twin Study 
Growing evidence has linked posttraumatic stress disorder (PTSD) to insulin resistance and type-2 diabetes, but most previous studies were cross-sectional. We examined the association between PTSD and incidence of diabetes in a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Lifetime PTSD was diagnosed at baseline with the Diagnostic Interview Schedule (DIS) according to DSM-III-R criteria. Subthreshold PTSD was defined by meeting some, but not all, criteria for PTSD. A total of 4,340 respondents without self-reported diabetes at baseline were included. Of these, 658 reported a new diagnosis of treated diabetes over a median of 19.4 years of follow-up. At baseline, twins with PTSD showed more behavioral and metabolic risk factors such as overweight and hypertension. The age-adjusted cumulative incidence of diabetes was significantly higher in twins with PTSD (18.9%) than those without PTSD (14.4%), [odds ratio (OR)=1.4, 95% confidence interval (CI) 1.03-1.8], and intermediate in those with subthreshold PTSD (16.4%) (OR=1.2, 95% CI 0.9-1.5, p for trend=0.03). Adjustment for military, lifestyle and metabolic factors diminished the association. No significant association was found comparing twin pairs discordant for PTSD. In conclusion, PTSD was prospectively associated with a 40% increased risk of new-onset type-2 diabetes which was partially explained by a cluster of metabolic and behavioral risk factors known to influence insulin resistance. Shared biological or behavioral precursors which occur within families may lead to both PTSD and insulin resistance/diabetes. Thus, PTSD could be a marker of neuroendocrine and metabolic dysregulation which may lead to type-2 diabetes.
PMCID: PMC4086302  PMID: 24950602
Posttraumatic Stress Disorder; Diabetes; Twin Studies; Epidemiology; Stress
4.  Posttraumatic Stress Disorder and Incidence of Coronary Heart Disease: A Twin Study 
Journal of the American College of Cardiology  2013;62(11):10.1016/j.jacc.2013.04.085.
To determine whether posttraumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD.
It has long been hypothesized that PTSD increases the risk of CHD but empirical evidence using objective measures is limited.
We conducted a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Among twin pairs without self-reported CHD at baseline, we selected pairs discordant for a lifetime history of PTSD, pairs discordant for a lifetime history of major depression, and pairs without either condition. All underwent a clinic visit after a median follow-up of 13 years. Outcomes included clinical events (myocardial infarction, other hospitalizations for CHD and coronary revascularization) and quantitative measures of myocardial perfusion by [N13] positron emission tomography, including a stress total severity score (STSS) and coronary flow reserve (CFR).
A total of 562 twins (281 pairs) were included with mean age of 42.6 yrs at baseline. The incidence of CHD was more than double in twins with PTSD (22.6%) than those without PTSD (8.9%; p<0.001). The association remained robust after adjusting for lifestyle factors, other CHD risk factors and major depression (OR=2.2, 95% confidence interval, 1.2-4.1). STSS was significantly higher (+ 95%, p=0.001) and CFR lower (−0.21, p=0.02) in twins with PTSD than those without, denoting worse myocardial perfusion. Associations were only mildly attenuated within 117 twin pairs discordant for PTSD.
Among Vietnam era veterans, PTSD is a risk factor for CHD.
PMCID: PMC3823367  PMID: 23810885
cardiovascular diseases; risk factors; epidemiology; stress
5.  Longitudinal associations between incident lumbar spine MRI findings and chronic low back pain or radicular symptoms: retrospective analysis of data from the longitudinal assessment of imaging and disability of the back (LAIDBACK) 
There are few longitudinal cohort studies examining associations between incident MRI findings and incident spine-related symptom outcomes. Prior studies do not discriminate between the two distinct outcomes of low back pain (LBP) and radicular symptoms. To address this gap in the literature, we conducted a secondary analysis of existing data from the Longitudinal Assessment of Imaging and Disability of the Back (LAIDBACK). The purpose of this study was to examine the association of incident lumbar MRI findings with two specific spine-related symptom outcomes: 1) incident chronic bothersome LBP, and 2) incident radicular symptoms such as pain, weakness, or sensation alterations in the lower extremity.
The original LAIDBACK study followed 123 participants without current LBP or sciatica, administering standardized MRI assessments of the lumbar spine at baseline and at 3-year follow-up, and collecting information on participant-reported spine-related symptoms and signs every 4 months for 3 years. These analyses examined bivariable and multivariable associations between incident MRI findings and symptom outcomes (LBP and radicular symptoms) using logistic regression.
Three-year cumulative incidence of new MRI findings ranged between 2 and 8%, depending on the finding. Incident annular fissures were associated with incident chronic LBP, after adjustment for prior back pain and depression (adjusted odds ratio [OR] 6.6; 95% confidence interval [CI] 1.2-36.9). All participants with incident disc extrusions (OR 5.4) and nerve root impingement (OR 4.1) reported incident radicular symptoms, although associations were not statistically significant. No other incident MRI findings showed large magnitude associations with symptoms.
Even when applying more specific definitions for spine-related symptom outcomes, few MRI findings showed large magnitude associations with symptom outcomes. Although incident annular fissures, disc extrusions, and nerve root impingement were associated with incident symptom outcomes, the 3-year incidence of these MRI findings was extremely low, and did not explain the vast majority of incident symptom cases.
PMCID: PMC4024651  PMID: 24886265
Sciatica; Annular; Tear; Fissure; Herniation; Bulge; Impingement; Endplate; Modic; Stenosis; Extrusion; Spondylolisthesis; Facet; Arthritis; Zygapophyseal; Disc
6.  MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample 
BMC Medical Genetics  2012;13:100.
Atherosclerosis is a complex process involving both genetic and epigenetic factors. The monoamine oxidase A (MAOA) gene regulates the metabolism of key neurotransmitters and has been associated with cardiovascular risk factors. This study investigates whether MAOA promoter methylation is associated with atherosclerosis, and whether this association is confounded by familial factors in a monozygotic (MZ) twin sample.
We studied 84 monozygotic (MZ) twin pairs drawn from the Vietnam Era Twin Registry. Carotid intima-media thickness (IMT) was measured by ultrasound. DNA methylation in the MAOA promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The association between DNA methylation and IMT was first examined by generalized estimating equation, followed by matched pair analyses to determine whether the association was confounded by familial factors.
When twins were analyzed as individuals, increased methylation level was associated with decreased IMT at four of the seven studied CpG sites. However, this association substantially reduced in the matched pair analyses. Further adjustment for MAOA genotype also considerably attenuated this association.
The association between MAOA promoter methylation and carotid IMT is largely explained by familial factors shared by the twins. Because twins reared together share early life experience, which may leave a long-lasting epigenetic mark, aberrant MAOA methylation may represent an early biomarker for unhealthy familial environment. Clarification of familial factors associated with DNA methylation and early atherosclerosis will provide important information to uncover clinical correlates of disease.
PMCID: PMC3532355  PMID: 23116433
DNA methylation; MAOA; Carotid atherosclerosis; Monozygotic twins; Familial factors

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