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Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study—the Fort Campbell Cohort study—examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (N = 473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90–180 days post deployment (random forest: AUC = 0.78, 95% CI = 0.67–0.89, sensitivity = 0.78, specificity = 0.71; SVM: AUC = 0.88, 95% CI = 0.78–0.98, sensitivity = 0.89, specificity = 0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUC = 0.85, 95% CI = 0.75–0.96, sensitivity = 0.88, specificity = 0.69; SVM: AUC = 0.87, 95% CI = 0.79–0.96, sensitivity = 0.80, specificity = 0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.

Network-based approaches to identifying gene expression signatures of disease have been shown to be more reproducible, accurate, and biologically informative than single-gene markers. Differential expression statistics are most commonly used to rank and select nodes within biological networks. Disease heterogeneity and disease-specific mechanisms may create changes in gene expression distributions that are not captured by differential expression analysis. We implemented a disease network identification algorithm using four unique statistical metrics, based on changes in mean expression, expression variance, and overall expression distribution changes. Using three publicly available gene expression datasets, we evaluated the size, strength, and disease classification performance of the identified subnetworks in cancer and Posttraumatic Stress Disorder (PTSD) cohorts. Identified subnetworks for all three datasets had significant enrichment of disease signal over individual genes, based on ${p}$ -value. Further, novel and unique subnetworks were identified by each statistical metric, including changes in expression variance related to BRCA1 in breast cancer, and changes in blood coagulation in PTSD. Subnetwork-based biomarkers also slightly improved prediction performance over individual gene markers. This approach could provide a novel network-based framework for understanding and predicting gene expression signals of disease.

Attempts to correlate blood levels of brain-derived neurotrophic factor (BDNF) with post-traumatic stress disorder (PTSD) have provided conflicting results. Some studies found a positive association between BDNF and PTSD diagnosis and symptom severity, while others found the association to be negative. The present study investigated whether serum levels of BDNF are different cross-sectionally between combat trauma-exposed veterans with and without PTSD, as well as whether longitudinal changes in serum BDNF differ as a function of PTSD diagnosis over time. We analyzed data of 270 combat trauma-exposed veterans (230 males, 40 females, average age: 33.29 ± 8.28 years) and found that, at the initial cross-sectional assessment (T0), which averaged 6 years after the initial exposure to combat trauma (SD=2.83 years), the PTSD positive group had significantly higher serum BDNF levels than the PTSD negative controls [31.03 vs. 26.95 ng/mL, t(268) = 3.921, p

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6–10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819–0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.

Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.

Posttraumatic stress disorder (PTSD) is associated with impaired major domains of psychology and behavior. Individuals with PTSD also have increased co-morbidity with several serious medical conditions, including autoimmune diseases, cardiovascular disease, and diabetes, raising the possibility that systemic pathology associated with PTSD might be identified by metabolomic analysis of blood. We sought to identify metabolites that are altered in male combat veterans with PTSD. In this case-control study, we compared metabolomic profiles from age-matched male combat trauma-exposed veterans from the Iraq and Afghanistan conflicts with PTSD (n = 52) and without PTSD (n = 51) ('Discovery group'). An additional group of 31 PTSD-positive and 31 PTSD-negative male combat-exposed veterans was used for validation of these findings ('Test group'). Plasma metabolite profiles were measured in all subjects using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified key differences between PTSD subjects and controls in pathways related to glycolysis and fatty acid uptake and metabolism in the initial 'Discovery group', consistent with mitochondrial alterations or dysfunction, which were also confirmed in the 'Test group'. Other pathways related to urea cycle and amino acid metabolism were different between PTSD subjects and controls in the 'Discovery' but not in the smaller 'Test' group. These metabolic differences were not explained by comorbid major depression, body mass index, blood glucose, hemoglobin A1c, smoking, or use of analgesics, antidepressants, statins, or anti-inflammatories. These data show replicable, wide-ranging changes in the metabolic profile of combat-exposed males with PTSD, with a suggestion of mitochondrial alterations or dysfunction, that may contribute to the behavioral and somatic phenotypes associated with this disease.

Accurate classification of biological phenotypes is an essential task for medical decision making. The selection of subjects for classifier training and validation sets is a crucial step within this task. To evaluate the impact of two approaches for subject selection—randomization and clinical balancing, we applied six classification algorithms to a highly replicated publicly available breast cancer data set. Using six performance metrics, we demonstrate that clinical balancing improves both training and validation performance for all methods on average. We also observed a smaller discrepancy between training and validation performance. Furthermore, a simple analytical argument is presented which suggests that we need only two metrics from the class of metrics based on the entries of the confusion matrix. In light of our results, we recommend: 1) clinical balancing of training and validation data to improve signal-to-noise ratio and 2) the use of multiple classification algorithms and evaluation metrics for a comprehensive evaluation of the decision making process.

Post-traumatic stress disorder (PTSD) is a psychological disorder affecting individuals that have experienced life-changing traumatic events. The symptoms of PTSD experienced by these subjects-including acute anxiety, flashbacks, and hyper-arousal-disrupt their normal functioning. Although PTSD is still categorized as a psychological disorder, recent years have witnessed a multi-directional research effort attempting to understand the biomolecular origins of the disorder. This review begins by providing a brief overview of the known biological underpinnings of the disorder resulting from studies using structural and functional neuroimaging, endocrinology, and genetic and epigenetic assays. Next, we discuss the systems biology approach, which is often used to gain mechanistic insights from the wealth of available high-throughput experimental data. Finally, we provide an overview of the current computational tools used to decipher the heterogeneous types of molecular data collected in the study of PTSD.

Thermochemistry of gas-phase ion-water clusters together with estimates of the hydration free energy of the clusters and the water ligands are used to calculate the hydration free energy of the ion. Often the hydration calculations use a continuum model of the solvent. The primitive quasichemical approximation to the quasichemical theory provides a transparent framework to anchor such efforts. Here we evaluate the approximations inherent in the primitive quasichemical approach and elucidate the different roles of the bulk medium. We find that the bulk medium can stabilize configurations of the cluster that are usually not observed in the gas phase, while also simultaneously lowering the excess chemical potential of the ion. This effect is more pronounced for soft ions. Since the coordination number that minimizes the excess chemical potential of the ion is identified as the optimal or most probable coordination number, for such soft ions, the optimum cluster size and the hydration thermodynamics obtained without account of the bulk medium on the ion-water clustering reaction can be different from those observed in simulations of the aqueous ion. The ideas presented in this work are expected to be relevant to experimental studies that translate thermochemistry of ion-water clusters to the thermodynamics of the hydrated ion and to evolving theoretical approaches that combine high-level calculations on clusters with coarse-grained models of the medium.