Christopher W. Forsberg

Testosterone Treatment and Mortality in Men with Low Testosterone Levels

CONTEXT Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known. OBJECTIVE The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels. DESIGN This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori. SETTING The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers. PATIENTS Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [≤250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005. MAIN OUTCOME MEASURE Total mortality in testosterone-treated compared with untreated men was measured. RESULTS Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42-0.88; P = 0.008). No significant effect modification was found by age, diabetes, or coronary heart disease. CONCLUSIONS In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment. These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels.

Post-traumatic stress disorder and incidence of coronary heart disease: a twin study.

OBJECTIVES The aim of this study was to determine whether post-traumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD. BACKGROUND It has long been hypothesized that PTSD increases the risk of CHD, but empirical evidence using objective measures is limited. METHODS 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 [(13)N] ammonia positron emission tomography, including a stress total severity score and coronary flow reserve. RESULTS A total of 562 twins (281 pairs) with a mean age of 42.6 years at baseline were included in this study. The incidence of CHD was more than double in twins with PTSD (22.6%) than in those without PTSD (8.9%; p < 0.001). The association remained robust after adjusting for lifestyle factors, other risk factors for CHD, and major depression (odds ratio: 2.2; 95% confidence interval: 1.2 to 4.1). Stress total severity score was significantly higher (+95%, p = 0.001) and coronary flow reserve was lower (-0.21, p = 0.02) in twins with PTSD than in those without PTSD, denoting worse myocardial perfusion. Associations were only mildly attenuated in 117 twin pairs discordant for PTSD. CONCLUSIONS Among Vietnam-era veterans, PTSD is a risk factor for CHD.

A twin study of the association between ptsd symptoms and rheumatoid arthritis

Objectives: To assess the association between posttraumatic stress disorder (PTSD) and rheumatoid arthritis (RA) and to determine if this was due to PTSD or confounding by environmental and genetic factors. Methods: Data were obtained from 3143 twin pairs in the Vietnam Era Twin Registry, which included male twin pairs who served during the Vietnam War era (mean age, 40.6 years; standard deviation, 2.9). Measurements included a PTSD symptom scale, history of physician-diagnosed RA, sociodemographics, and health confounding factors. Co-twin control analytic methods used generalized estimating equation logistic regression to account for the paired twin data and to examine the association between PTSD symptoms and RA in all twins. Separate analyses were conducted within twin pairs. Results: The prevalence of RA among this population was 1.9% (95% confidence interval, 1.6–2.3) and the mean PTSD symptom level was 25.5 (standard deviation, 9.6). PTSD symptoms were associated with an increased likelihood of adult RA even after adjustment for confounding (ptrend < .001). Among all twins, those in the highest PTSD symptom quartile were 3.8 times more likely (95% confidence interval, 2.1–6.1) to have RA compared with those in the lowest. These findings also persist when examined within twin pairs (ptrend < .022). Conclusions: PTSD symptoms were associated with adult RA onset. Even after adjustment for familial/genetic factors and other confounders, an association between PTSD symptoms and RA remained. This is one of the first studies to demonstrate a link between PTSD and RA onset among a community-based population sample, independent of familial and genetic factors. PTSD = posttraumatic stress disorder; RA = rheumatoid arthritis; VET = Vietnam Era Twin; GEE = generalized estimating equation; MZ = monozygotic; DZ = dizygotic; BMI = body mass index.

Racial Differences in the Evaluation and Treatment of Hepatitis C Among Veterans: A Retrospective Cohort Study

OBJECTIVES We examined the association between race and hepatitis C virus (HCV) evaluation and treatment of veterans in the Northwest Network of the Department of Veterans Affairs (VA). METHODS In our retrospective cohort study, we used medical records to determine antiviral treatment of 4263 HCV-infected patients from 8 VA medical centers. Secondary outcomes included specialty referrals, laboratory evaluation, viral genotype testing, and liver biopsy. Multiple logistic regression was used to adjust for clinical (measured through laboratory results and International Classification of Diseases, Ninth Revision, codes) and sociodemographic factors. RESULTS Blacks were less than half as likely as Whites to receive antiviral treatment (odds ratio [OR]=0.38; 95% confidence interval [CI]=0.23, 0.63). Both had similar odds of referral and liver biopsy. However, Blacks were significantly less likely to have complete laboratory evaluation (OR=0.67; 95% CI=0.52, 0.88) and viral genotype testing (OR=0.68; 95% CI=0.51, 0.90). CONCLUSIONS Race is associated with receipt of medical care for various medical conditions. Further investigation is warranted to help understand whether patient preference or provider bias may explain why HCV-infected Blacks were less likely to receive medical care than Whites.

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)

BackgroundThere 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.MethodsThe 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.ResultsThree-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.ConclusionsEven 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.

Determining Zygosity in the Vietnam Era Twin Registry: An Update

Our work assessed the accuracy of the original zygosity classification in the Vietnam Era Twin (VET) Registry using new information from DNA markers on a subset of participants. We then constructed an updated zygosity classification algorithm. The VET Registry includes 7,375 male-male twin pairs who served in the military during the Vietnam era. During the mid-1980s 4,774 twin pairs completed a zygosity questionnaire of 20 items. Additionally, military record information, including blood group, was available. Items from the zygosity questionnaire and blood group were used in the original zygosity classification. Between 1990-2009 DNA was obtained from 612 twin pairs and concordance between co-twins was used to classify zygosity. Next logistic regression was used to construct predicted probabilities of zygosity using items from the zygosity questionnaire with this subsample. All twins were reclassified according to the new zygosity prediction model and compared with the original zygosity assignment. The original and new predicted probabilities of zygosity were highly correlated (r = 0.962) and concordance for the classification of zygosity was similarly high (kappa = 0.936). Errors in the original zygosity assignment were primarily due to monozygotic twins that were misclassified as dizygotic based on military record blood group data. Removing the military record blood group data markedly improved the accuracy of the original classification. Zygosity assignment based on a zygosity questionnaire was highly predictive of DNA-based zygosity. Augmentation of such a zygosity classification from administrative data, military records, or other records, should be done with caution.

The Vietnam Era Twin Registry: a quarter century of progress.

Now celebrating its 26th year of existence, the Vietnam Era Twin Registry continues to be one of the largest national samples of adult twins in the United States. The Registry twin member population is composed of 7,369 US male-male twin pair Veterans (14,738 total individuals) who served on active duty in the military during the Vietnam conflict (1964-1975). The Registry also maintains a register, data repository, and a biospecimen repository. Details on the operations of the Registry are described, as well as an overview of specific studies. Registry maintenance activities are also described, including the updating of contact information and vital status. Future plans include expanding the biospecimen repository and obtaining input from twins about study methods and diseases and conditions they would like to see investigated.

Long-Term Trajectories of PTSD in Vietnam-Era Veterans: The Course and Consequences of PTSD in Twins

We estimated the temporal course of posttraumatic stress disorder (PTSD) in Vietnam-era veterans using a national sample of male twins with a 20-year follow-up. The complete sample included those twins with a PTSD diagnostic assessment in 1992 and who completed a DSM-IV PTSD diagnostic assessment and a self-report PTSD checklist in 2012 (n = 4,138). Using PTSD diagnostic data, we classified veterans into 5 mutually exclusive groups, including those who never had PTSD, and 4 PTSD trajectory groups: (a) early recovery, (b) late recovery, (c) late onset, and (d) chronic. The majority of veterans remained unaffected by PTSD throughout their lives (79.05% of those with theater service, 90.85% of those with nontheater service); however, an important minority (10.50% of theater veterans, 4.45% of nontheater veterans) in 2012 had current PTSD that was either late onset (6.55% theater, 3.29% nontheater) or chronic (3.95% theater, 1.16% nontheater). The distribution of trajectories was significantly different by theater service (p < .001). PTSD remains a prominent issue for many Vietnam-era veterans, especially for those who served in Vietnam.

MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample

BackgroundAtherosclerosis 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.MethodsWe 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.ResultsWhen 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.ConclusionsThe 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.

Long-Term Trajectories of PTSD in Vietnam-Era Veterans

We estimated the temporal course of posttraumatic stress disorder (PTSD) in Vietnam-era veterans using a national sample of male twins with a 20-year follow-up. The complete sample included those twins with a PTSD diagnostic assessment in 1992 and who completed a DSM-IV PTSD diagnostic assessment and a self-report PTSD checklist in 2012 (n = 4,138). Using PTSD diagnostic data, we classified veterans into 5 mutually exclusive groups, including those who never had PTSD, and 4 PTSD trajectory groups: (a) early recovery, (b) late recovery, (c) late onset, and (d) chronic. The majority of veterans remained unaffected by PTSD throughout their lives (79.05% of those with theater service, 90.85% of those with nontheater service); however, an important minority (10.50% of theater veterans, 4.45% of nontheater veterans) in 2012 had current PTSD that was either late onset (6.55% theater, 3.29% nontheater) or chronic (3.95% theater, 1.16% nontheater). The distribution of trajectories was significantly different by theater service (p < .001). PTSD remains a prominent issue for many Vietnam-era veterans, especially for those who served in Vietnam.