Civilian Cohorts Research Articles

Extremity War Injury Symposium 2024: Sports Medicine and Medical Readiness Section Summary

Collaboration between military and civilian investigators is necessary to develop strategies for optimizing treatments to diminish the sequelae of non–battle-related musculoskeletal injuries, which are highly prevalent among servicemembers. The 2024 Extremity War Injuries Symposium provided a forum whereby a diverse group of clinicians and researchers could develop strategies for optimizing treatments and diminishing the sequelae of conditions that are highly prevalent among active individuals. Key points were as follows: 1. The value of collaborations between military and civilian investigators cannot be overemphasized. These synergies can leverage the capabilities of established infrastructures in order to answer important questions pertaining to short-term outcomes—for example, warrior readiness of anterior cruciate ligament reconstructions among servicemembers and long-term posttraumatic osteoarthritis (PTOA) outcomes among civilian cohorts. 2. Current and future prospective trials will inform future treatment decisions related to multiligamentous knee injuries and glenohumeral instability. 3. Novel approaches to addressing PTOA in the acute postinjury period will need longitudinal surveillance to measure their impact on improving clinical outcomes and diminishing residual functional deficits.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts

BackgroundIncorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not.MethodsElastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts.ResultsThe eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD.ConclusionThe inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts.

Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

Comparison of different definitions of traumatic brain injury: implications for cohort characteristics and survival in women, Philadelphia, USA

BackgroundTraumatic brain injury (TBI) is an acute injury that is understudied in civilian cohorts, especially among women, as TBI has historically been considered to be largely a condition of athletes...

Genome-Wide Meta-Analysis of DNA Methylation and PTSD in 23 Military and Civilian Cohorts and Multi-Omic Analysis Point Toward Immune Mechanisms

Genome-Wide Meta-Analysis of DNA Methylation and PTSD in 23 Military and Civilian Cohorts and Multi-Omic Analysis Point Toward Immune Mechanisms

Epigenome-Wide Meta-Analysis of 11 Military and Civilian Cohorts Reveals Cell-Type Specific and Inflammatory DNA Methylation Patterns Associated With PTSD

Epigenome-Wide Meta-Analysis of 11 Military and Civilian Cohorts Reveals Cell-Type Specific and Inflammatory DNA Methylation Patterns Associated With PTSD

Psychosocial treatments for nightmares in adults and children: a systematic review

BackgroundAs nightmares may be a risk factor for, or symptom of, multiple psychological disorders, some researchers suggest that nightmares should be screened, diagnosed, and treated. Treatments for nightmares include trauma-focused Cognitive Behavioural Therapy and Image Rehearsal Therapy, and pharmacological interventions such as prazosin and nitrazepam. As recent research has put into question our current understanding of treatment efficacy, there is a need to systematically review findings related to the effectiveness of nightmare treatments to inform best practice. The current review assessed the efficacy of psychosocial treatments of nightmare in all cohorts.MethodsA systematic search of four databases for peer reviewed journal articles from 2000 onwards produced 69 (35 RCTs, 34 non-RCTs) eligible articles that underwent narrative synthesis.ResultsThe results provide strong evidence for exposure and image rehearsal treatments for the reduction of nightmare frequency, severity, and distress, in civilian, military, idiopathic, and posttraumatic stress disorder (PTSD) cohorts. There is emerging evidence that self-guided and brief treatment modalities offer efficient and effective treatment options. There is an urgent need for clinical trials of treatment effectiveness in children.ConclusionsThe results suggest that treatments for nightmares are most effective when they facilitate a sense of control or mastery by directly targeting the nightmare content and/or the client’s emotional responses to the nightmare content.Trial registrationA review protocol was registered with PROSPERO (CRD42020204861).

Blood-Based DNA Methylation and Exposure Risk Score Predicts PTSD With High Accuracy in Military and Civilian Cohorts

Blood-Based DNA Methylation and Exposure Risk Score Predicts PTSD With High Accuracy in Military and Civilian Cohorts

Epigenome-Wide Meta-Analysis of 13 Military and Civilian Cohorts Reveals Common and Cell-Type Specific DNA Methylation Patterns Associated With PTSD

Epigenome-Wide Meta-Analysis of 13 Military and Civilian Cohorts Reveals Common and Cell-Type Specific DNA Methylation Patterns Associated With PTSD

Elevated Kinesiophobia Is Associated With Reduced Recovery From Lower Extremity Musculoskeletal Injuries in Military and Civilian Cohorts.

The purpose of this study was to examine associations between level of kinesiophobia and improvement in physical function during recovery from lower extremity injury. A total 430 adults (mean [SD]: age = 27.3 [6.4] years; sex = 70.5% men; body mass index = 27.6 [5.2] kg/m2) were included in the analyses. Using the Patient-Reported Outcomes Measurement Information System, physical function was evaluated in parallel with treatment from a physical therapist at the initial visit and every 3weeks until final visit or up to 6months. A Tampa Scale of Kinesiophobia (TSK-17) score of >41 indicated elevated TSK. Four TSK groups were identified: (1) TSK score improved from >41 at initial visit to <41 by final visit (TSK_I), (2) TSK score was <41 at initial and final visits (TSK-), (3) TSK score was >41 at initial and final visits (TSK+), and (4) TSK score worsened from <41 at initial visit to ≥41 by final visit (TSK_W). Linear mixed effects models were used to examine differences between groups in improved physical function over time, with adjustment for depression and self-efficacy. Groups with elevated kinesiophobia at the final visit had smaller positive improvements in physical function (mean change [95% CI]: TSK+ = 7.1 [4.8-9.4]; TSK_W: 6.0 [2.6-9.4]) compared with groups without elevated kinesiophobia at the final visit (TSK_I = 9.8 [6.4-13.3]; TSK- = 9.7 [8.1-11.3]) by 12 weeks. Elevated kinesiophobia that persists or develops over the course of care is associated with less improvement in physical function within military and civilian cohorts. The findings of this prospective longitudinal study support the need to assess for elevated kinesiophobia throughout the course of care because of its association with decreased improvement in physical function. To help improve your physical function, your physical therapist can monitor the interaction between fear of movement and your clinical outcomes over the course of treatment.

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Epidemiology of Symptomatic Dorsal Wrist Ganglia in Active Duty Military and Civilian Populations

PurposeThe epidemiology of dorsal wrist ganglia (DWG) has been poorly studied. The purpose of this study was to determine the epidemiology of DWG in the US military and civilian populations. We hypothesized that military service would be associated with an increased risk for developing a DWG.MethodsThe US Department of Defense Management Analysis and Reporting Tool, a database of health care encounters by military personnel and dependents, was queried for encounters with an International Classification of Diseases, Ninth Revision diagnosis of 727.41 (ganglion of a joint) or 727.43 (ganglion, unspecified location) between 2009 and 2014. There is no specific code for DWG, so a random sample of 1,000 patients was selected from both the military and civilian cohorts. These 2,000 electronic medical records were examined to identify patients with a DWG. This estimate was used to determine the unadjusted incidence of DWG with a 95% confidence interval and a 5% margin of error in the entire military and civilian dependent population. Adjusted incidence rates and incidence rate ratios (IRR) were determined using Poisson regression, controlling for demographic covariates.ResultsThe incidence of DWG in the military population is 14.25/10,000 person-years compared with 7.01/10,000 person-years in the civilian population. Female sex was a significant risk factor in both the military (IRR, 2.59) and civilian populations (IRR, 2.26). Younger age group (age 25–34 years) was a significant risk factor for DWG compared with an older age group (age 45–64 years) in both the military (IRR, 1.74) and civilian populations (IRR, 2.56). Senior rank (both officer and enlisted) was a significant risk factor for DWG compared with junior rank (IRR, 1.95).ConclusionsThe incidence of DWG was higher in the military compared with the civilian population. There is a higher incidence of a DWG in females and in the senior ranks (both officer and enlisted).Type of study/level of evidencePrognostic III.

Military-Specific Normative Data for Cognitive and Motor Single- and Dual-Task Assessments for Use in Mild Traumatic Brain Injury Assessment.

Military personnel and civilian athletes are both at risk for mild traumatic brain injury. However, these groups are unique in their training and typical daily activities. A fundamental gap in the evaluation of military personnel following mild traumatic brain injury is the lack of military-specific normative reference data. This project aimed to determine if a separate normative sample should be used for military personnel on their performance of the Cleveland Clinic Concussion application and a recently developed dual-task module. Data were collected from healthy military personnel (n=305) and civilians (n=281) 18 to 30years of age. Participants completed the following assessments: simple and choice reaction time, Trail Making tests A&B, processing speed test, single-task postural stability, single-task cognitive assessment, and dual-task assessment. Civilian participants outperformed military service members on all cognitive tasks under single- and dual-task conditions (P≤0.04). The military group outperformed civilians on all postural stability tasks under single- and dual-task conditions (P≤0.01). Differences in cognitive performance and postural stability measures may be influenced by demographic differences between military and civilian cohorts. Thus, military-specific normative datasets must be established to optimize clinical interpretation of Cleveland Clinic Concussion assessments.

Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pathophysiology. In the current study, we leveraged recent methodological advances to investigate sex-specific differences in DNAm-based leukocyte composition that are associated with lifetime PTSD. We estimated leukocyte composition on a combined methylation array dataset (483 participants, ∼450 k CpG sites) consisting of two civilian cohorts, the Detroit Neighborhood Health Study and Grady Trauma Project. Sex-stratified Mann-Whitney U test and two-way ANCOVA revealed that lifetime PTSD was associated with significantly higher monocyte proportions in males, but not in females (Holm-adjusted p-val < 0.05). No difference in monocyte proportions was observed between current and remitted PTSD cases in males, suggesting that this sex-specific difference may reflect a long-standing trait of lifetime history of PTSD, rather than current state of PTSD. Associations with lifetime PTSD or PTSD status were not observed in any other leukocyte subtype and our finding in monocytes was confirmed using cell estimates based on a different deconvolution algorithm, suggesting that our sex-specific findings are robust across cell estimation approaches. Overall, our main finding of elevated monocyte proportions in males, but not in females with lifetime history of PTSD provides evidence for a sex-specific difference in peripheral blood leukocyte composition that is detectable in methylomic profiles and that may reflect long-standing changes associated with PTSD diagnosis.

Analysis of Genetically Regulated Gene Expression Identifies a Trauma Type Specific PTSD Gene, SNRNP35

PTSD has significant genetic heritability; however, it is unclear how genetic risk influences tissue-specific gene expression. We used brain and non-brain transcriptomic imputation models to impute genetically regulated gene expression (GReX) in 9,087 PTSD-cases and 23,811 controls and identified thirteen significant GReX-PTSD associations. The results suggest substantial genetic heterogeneity between civilian and military PTSD cohorts. The top study-wide significant PTSD-association was with predicted downregulation of the Small Nuclear Ribonucleoprotein U11/U12 Subunit 35 (SNRNP35) in the BA9 region of the prefrontal cortex (PFC) in military cohorts. In peripheral leukocytes from 175 U.S. Marines, the observed PTSD differential gene expression correlated with the predicted blood GReX differences for these individuals, and deployment stress downregulated SNRNP35 expression, primarily in Marines with post-deployment PTSD. SNRNP35 is a subunit of the minor spliceosome complex and SNRNP35 knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis in mice downregulated PFC Snrnp35 expression.

Low-level cognitive ability in young adulthood and other risk factors of depression in an observational cohort study among deployed Danish soldiers

PurposeEvidence exists of an association between pre-morbid lower cognitive ability and higher risk of hospitalization for depressive disorder in civilian cohorts. The purpose of this study was to examine the relationship of cognitive ability at conscription with post-deployment depression and the influence of (1) baseline factors: age, gender, and pre-deployment educational level, (2) deployment-related factors: e.g., war-zone stress and social support, and (3) co-morbid PTSD.MethodsAn observational cohort study linking conscription board registry data with post-deployment self-report data. The study population consisted of Danish Army military personnel deployed to different war zones from 1997 to 2015. The association between cognitive ability at conscription and post-deployment depression was analyzed using repeated-measure logistic regression models.ResultsStudy population totaled 9716 with a total of 13,371 deployments. Low-level cognitive ability at conscription was found to be weakly associated with post-deployment probable depression after adjustment for more important risk factors like gender, education, and deployment-related factors [odds ratio (OR) 0.93, 95% confidence interval (CI) 0.88–0.99]. The co-occurrence rate with PTSD was nearly 60%. When adding co-morbid PTSD as an independent variable, the association between cognitive ability and probable depression became insignificant, OR 0.95, CI 0.89–1.02.ConclusionsLow cognitive ability at conscription is a risk factor for depression among returning military personnel, but unimportant compared to gender, education, and deployment-related factors. Part of this effect may be related to co-morbid PTSD. Use of cognitive ability score as an isolated selection tool cannot be recommended because of low predictive performance.

Epigenetic Biomarkers Of PTSD: Updates From The EWAS Working Group of The PTSD PGC

Trauma exposure is unfortunately quite common, yet only a minority of individuals develop PTSD following trauma. The Epigenome-Wide Association Study (EWAS) group of the PTSD PGC is working to identify DNA methylation-based epigenetic biomarkers of PTSD that can serve as important indicators of the disorder, and to characterize which of these biomarkers identify individuals who may be most at risk following trauma. Existing, blood-derived DNA methylation microarray data from three civilian and seven military cohorts were analyzed using a common pipeline that tested each CpG site for an association with PTSD, controlling for age, genomic-derived ancestry estimates, leukocyte cell proportions as well as study-specific covariates if applicable (i.e. gender, plate, or bisulfite conversion). A meta-analysis across all cohorts and separately within Civilian and Military cohorts was subsequently conducted to identify robust biomarkers of PTSD. Results from primary analyses of all 1,896 samples revealed that the top four CpG sites fell within the AHRR locus (FDR for all sites <0.0003) and were all associated with reduced DNA methylation in PTSD. However, the associations at all four sites were substantially attenuated (FDR for all sites >0.69) in additional analyses that controlled for smoking. In contrast, the fifth ranked CpG site within RNF6 (FDR=0.007) from the primary analyses became the top-ranked CpG site associated with PTSD in our additional analyses that controlled for smoking (N=1,841), although results did not reach statistical significance (FDR=0.09). The meta-analysis of Civilian cohorts (N = 545) yielded two significant CpG sites within the NRG1 (FDR = 0.023) and HGS (FDR = 0.033) loci. Both loci remained significant after controlling for smoking. A sensitivity analysis of two cohorts found that the association with PTSD was consistent within each cohort after controlling for childhood maltreatment. Longitudinal analyses are ongoing to assess whether these differences pre-date trauma exposure that precipitates PTSD, or whether they associate with PTSD onset.

The Psychiatric Genomics Consortium For PTSD: Integration of Multi-System Markers of Risk And Resilience

Overall Abstract The Psychiatric Genomics Consortium for PTSD (PGC-PTSD) is the largest international effort focused on understanding the genomic and epigenomic architecture of PTSD. We have now aggregated genomic data from over 50 studies, including ~20,000 PTSD cases and over 50,000 trauma-exposed controls of diverse ancestries and traumatic events to conduct well-powered genome-wide association studies (GWAS) of PTSD. By expanding on this initial effort, we have leveraged our organizational structure to move beyond SNP-based associations with closely connected working groups centered on CNV analyses, epigenetics, gene expression, and intermediate phenotypes such as neuroimaging, psychophysiology, and physical health. An overarching theme across working groups includes sex-specific differences in PTSD risk and vulnerability. This symposium will first present our current GWAS results from the PGC-PTSD freeze 2 that highlight the genetic vulnerability for developing PTSD following trauma exposure, including SNP-based heritability and genetic correlation across psychiatric disorders and other phenotypes / traits of interest. Next, we will present epigenome-wide effects on risk of developing PTSD across civilian and military cohorts. The second half of the symposium will focus on findings from intermediate phenotypes and anthropometric traits. Our third talk will present neuroimaging data that reveals smaller amygdala and hippocampal volume in PTSD, particularly when exposed to childhood trauma. Lastly, we will present analyses investigating the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women, suggesting a putative causal relationship between genetically determined female body shape and PTSD. We will discuss our future strategies with a focus on harmonizing predictive variables such as trauma type, trauma severity, chronicity of exposure as well as outcome variables such as PTSD diagnoses, illness severity, and comorbid psychopathologies.

Two-year mortality and functional outcomes in combat-related penetrating brain injury: battlefield through rehabilitation.

OBJECTIVEThere are limited data concerning the long-term functional outcomes of patients with penetrating brain injury. Reports from civilian cohorts are small because of the high reported mortality rates (as high as 90%). Data from military populations suggest a better prognosis for penetrating brain injury, but previous reports are hampered by analyses that exclude the point of injury. The purpose of this study was to provide a description of the long-term functional outcomes of those who sustain a combat-related penetrating brain injury (from the initial point of injury to 24 months afterward).METHODSThis study is a retrospective review of cases of penetrating brain injury in patients who presented to the Role 3 Multinational Medical Unit at Kandahar Airfield, Afghanistan, from January 2010 to March 2013. The primary outcome of interest was Glasgow Outcome Scale (GOS) score at 6, 12, and 24 months from date of injury.RESULTSA total of 908 cases required neurosurgical consultation during the study period, and 80 of these cases involved US service members with penetrating brain injury. The mean admission Glasgow Coma Scale (GCS) score was 8.5 (SD 5.56), and the mean admission Injury Severity Score (ISS) was 26.6 (SD 10.2). The GOS score for the cohort trended toward improvement at each time point (3.6 at 6 months, 3.96 at 24 months, p > 0.05). In subgroup analysis, admission GCS score ≤ 5, gunshot wound as the injury mechanism, admission ISS ≥ 26, and brain herniation on admission CT head were all associated with worse GOS scores at all time points. Excluding those who died, functional improvement occurred regardless of admission GCS score (p < 0.05). The overall mortality rate for the cohort was 21%.CONCLUSIONSGood functional outcomes were achieved in this population of severe penetrating brain injury in those who survived their initial resuscitation. The mortality rate was lower than observed in civilian cohorts.

Epigenetic Meta-Analysis Across Three Civilian Cohorts Identifies NRG1 and HGS as Blood-Based Biomarkers for Post-Traumatic Stress Disorder

Trauma exposure is a necessary, but not deterministic, contributor to post-traumatic stress disorder (PTSD). Epigenetic factors may distinguish between trauma-exposed individuals with versus without PTSD. We conducted a meta-analysis of PTSD epigenome-wide association studies in trauma-exposed cohorts drawn from civilian contexts. Whole blood-derived DNA methylation levels were analyzed in 545 study participants, drawn from the three civilian cohorts participating in the PTSD working group of the Psychiatric Genomics Consortium. Two CpG sites significantly associated with current PTSD in NRG1 (cg23637605) and in HGS (cg19577098). PTSD is associated with differential methylation, measured in blood, within HGS and NRG1 across three civilian cohorts.