Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder

Abstract

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD

“…A set of two independent cohorts (with longitudinal repeat assessments in a subset of the first) totaling 215 male veterans from Operation Enduring Freedom (OEF) and/or Operation Iraqi Freedom (OIF) conflicts were recruited as part of our large SBC study [18,37] designed to identify biomarkers for PTSD diagnosis. Participants were recruited in two distinct cohorts, called the Discovery and Validation cohorts.…”

“…AgeAccelGrim has not yet been investigated in PTSD, even though PTSD may represent a condition of accelerated biological aging that is associated with excess medical morbidity and mortality [2]. Here we report results from the first investigation of epigenetic aging in PTSD using AgeAccelGrim, with both crosssectional and longitudinal data from two independent wellcharacterized male Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veteran cohorts from the PTSD Systems Biology Consortium (SBC) [18]. The results indicate PTSD is associated with higher AgeAccelGrim.…”

Feasibility and Efficacy of a Resiliency Intervention for the Prevention of Chronic Emotional Distress Among Survivor-Caregiver Dyads Admitted to the Neuroscience Intensive Care Unit

“…RT was developed to directly address limitations of prior negative trials in similar settings and with similar populations. 46,47…”

Predicting multi-modal symptom trajectories across 7 years in veterans with chronic posttraumatic stress

“…Unfortunately, the majority of longitudinal research studies have emphasized PTS, while omitting other potentially salient outcome indicators. Consequently, while an array of polygenic factors and biomarkers (6), internal resilience and risk factors (7)(8)(9), peritrauma conditions (4,10,11) and experiences (14), and sociodemographic factors (12) may explain disparities in veteran outcomes, most of this evidence relies on characterizing veteran outcomes in a single domain related to symptoms of PTS.…”