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

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The PTSD Systems Biology Consortium, Dean, Kelsey R., Hammamieh, Rasha, Mellon, Synthia H., Abu-Amara, Duna, Flory, Janine D., Guffanti, Guia, Wang, Kai +32 more·2020·Molecular Psychiatry
DOI 10.1038/s41380-019-0496-zPMC PMC7714692
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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.

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  • Efficient insulin action is essential for inhibition of proteolysis.

    “Efficient insulin action is essential for inhibition of proteolysis (17); therefore, insulin resistance would enhance the proteolytic effect adding to amino acid pool in the plasma.”

    From Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity (2019) · cites this paper as [17]

    The Results section lists insulin as a PTSD biomarker and notes increased insulin resistance in veterans with PTSD, but does not discuss insulin’s effect on proteolysis. Searches for insulin action, proteolysis, and plasma amino acids found no passage in our copy addressing the attributed claim; page numbers were unavailable. (LLM, conf=0.76)

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Authors
The PTSD Systems Biology Consortium, Dean, K. R., Hammamieh, R., Mellon, S. H., Abu-Amara, D., Flory, J. D., Guffanti, G., Wang, K., Daigle, B. J., Gautam, A., Lee, I., Yang, R., Almli, L. M., Bersani, F. S., Chakraborty, N., Donohue, D., Kerley, K., Kim, T.-K., Laska, E., Young Lee, M., Lindqvist, D., Lori, A., Lu, L., Misganaw, B., Muhie, S., Newman, J., Price, N. D., Qin, S., Reus, V. I., Siegel, C., Somvanshi, P. R., Thakur, G. S., Zhou, Y., Hood, L., Ressler, K. J., Wolkowitz, O. M., Yehuda, R., Jett, M., Doyle, F. J., & Marmar, C.
Affiliations
  • Harvard University (US)
  • United States Army Medical Research and Development Command (US)
  • University of California, San Francisco (US)
  • James J. Peters VA Medical Center (US)
  • McLean Hospital (US)
  • Institute for Systems Biology (US)
  • University of Memphis (US)
  • Frederick National Laboratory for Cancer Research (US)
  • Emory University (US)
  • The Geneva Foundation (US)
Corresponding author
Doyle, Francis J.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-09-10
Volume
25
Issue
12
Pages
3337-3349
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-019-0496-z
PMC
PMC7714692
OpenAlex
W2972380287
Cited by
101
References
6
Citations by year
2026: 10 · 2025: 7 · 2024: 16 · 2023: 13 · 2022: 18 · 2021: 12 · 2020: 23 · 2019: 2
FWCI
16.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
United States Department of Defense | United States Army | U.S. Army Research, Development and Engineering Command | Army Research Office (W911NF-13-1-0376, W911NF-17-2-0086, W911NF-18-2-0056, W911NF-17-1-0069)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Keywords
post-traumatic stress disorder, combat-related PTSD, diagnostic biomarkers, multi-omics integration, veterans, biomarker panel, polygenic risk, recursive feature elimination, support vector machine, diagnostic accuracy, military personnel
MeSH terms
Brain, Humans, Male, Military Personnel, Stress Disorders, Post-Traumatic, Veterans, Biomarkers

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