UNCLASSIFIED Dr Marti Jett ST Chief Scientists Systems Biology US Army Med Res amp Devel Com MRDC Fort Detrick MD 21701 Martijetttiltoncivmailmil Project lead scientists ID: 932698
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Slide1
Screening for early ID of PTSD
UNCLASSIFIED
Dr. Marti Jett, STChief Scientists, Systems BiologyUS Army Med Res & Devel. Com (MRDC)Fort Detrick, MD 21701Marti.jett-tilton.civ@mail.mil
Project lead scientists
Marti Jett Molecular
C
ores
Frank Doyle
Computational
Core
Charlie
Marmar
Clinical
Core
Slide2Material
has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of
Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25.Citations of commercial organizations or trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations. I have no real or apparent conflicts of interest to report.
Slide3Factors
Influencing Wellness
Genomics
Proteomics
Lipidomics
Metabolomics
Individual “
Exposome
”
Environmental Exposures
Sleep
Transcriptomics
Epigenomics
Individual Factors
Gender
Nutrition
Training
Education
Slide4Statistics for PTSD
4
Number of cases
: 10-15% of U.S. combat deployed Service Members develop PTSD symptoms (
Hoge
et al.
2004, Marmar
et al.
2009,
Vasterling
et al.
2010)
Evacuated
for Disease and Non-Battle Injury (DNBI)
:
1
(Afghanistan, Iraq, Syria in CY 2001 – 2018) 57,371 (54.1%) Evacuated
for: 1. Orthopedic injuries 14,193 (24.7%) 2. Neurology/Neurosurgery injuries 8,960 (15.6%)#1 diagnosis: “reaction to severe stress &
adjustment disorders” – PTSD later?
3. Psych Health
8,171 (14.2%)
Slide5PTSD Symptoms Checklist (SCL -90)
Difficulty doing/keeping their job (lack of sleep, uncontrolled anger, hypervigilance
etc)Family relationships disintegrateSomatization (pain with out an identifying organic cause and may not respond to medication)Metabolic syndrome (obesity/pre-diabetes)Self-destructive behavior and addictionDepression which may lead to Suicide Ideation
Slide6WHY is that important to the Military vs VA?
STIGMA
Perceived or actualAdmitting having issues typical of PTSD could block promotionsWith out promotions, they cannot re-enlist or continue their Military career.Some simply deny that what they are experiencing could be PTSDSome do not realize that what they are experiencing is PTSD
Slide7PTSD Systems Biology Consortium
7
Neuroimaging Core
NYU
(
Sodickson
)
UCSF
(
Weiner/Mueller
)
Multi-Omics Cores & Rodent studies
Integrative
Systems Biology
(
Jett/Hammamieh
)
Institute
for
Systems Biology
(
Hood, Wang, Lee
)
Clinical
and Neurocognitive
Cores
NYU
(
Marmar
,
Abu Amara and
Newman)
Neuroimaging is acquired for all participants
Neurogenetics
Core
Harvard & Emory
(
Ressler
)
Metabolism & Cell Aging
UCSF
(
Wolkowitz
/Mellon
)
Neuroendocrine
and
Clinical Core
Mt. Sinai; Bronx VA (Yehuda, Flory,
Makotkine
)
Blood is acquired
and processed for all participants
Machine learning/Bioinformatics
Core
Harvard University
(Doyle, Dean)
Slide8Director: Marti Jett, PhD
Deputy
Dir: Rasha Hammamieh, PhDProgrammatic Review24 June 2014 SYSTEMS BIOLOGY & CLINICAL APPROACH10. Microbiome 9. Neuroendocrine10. Blood chemistries11. Physiology12. Immunology13. Psychological profiles14. Clinical Records Forms
Slide9Sample Collection Rules
TIME OF DAY: 8-10 AM
Fasting for at least 4 hrRecord information about:Sleep the week/night before studyWhat and when the person last ateUnusual activitiesGeneral information about psychological status nowAll samples were aliquoted & preserved immediatelyUNCLASSIFIED
Slide101
ST
CLINICAL COHORT: GREATER NYC AREAVeterans-To obtain a stable phenotype
Baseline Diagnostic Clinical Interview (N=805)
Eligible (Male, N = 316)
(Female, N=41)
Not Eligible
(N=448)
(Lifetime PTSD only , PTSD Subthreshold , AUD,
PsychiatricDisorder
, Drug Dependence,
NeurologicDisorder
, TBI
Phone Pre-Screen Completed (N=1,990)
MALE DISCOVERY SET
82 PTSD
81 CONTROL
MALE RECALL SET
30 PTSD
29 CONTROL
MALE VALIDATION SET
28 PTSD
26 CONTROL
Slide11Procedure for data evaluation
UNCLASSIFIED
Slide12UNCLASSIFIED
Slide13Stage 1: Recursive Feature Elimination
Begin with a biomarker panel of all significant markers (
343 features)Remove one-by-one, and compute average AUC of n-1 markers over 50 rounds of biomarker validation using bootstrapped datasetsRemove the marker resulting in the largest AUC, down-selecting to a panel of size n-1Repeat steps 2&3 until a single biomarker remainsThe panel with the largest AUC was selectedStage 2: Variable Importance FilteringSort remaining features based on random forest variable importance
Select biomarkers with at least 30% of the maximum
feature
importance value
28
markers pass importance threshold
Candidate Biomarker Identification Approach
Slide14Classifier
Support Vector MachineLogistic regression
Tree-based boostingLinear Discriminant AnalysisPolygenic Risk ScoreRandom ForestLassoValidation Test Of Biomarker Panel #1
,
Molecular
Psychiatry. 15 Sept 2019
https://
doi.org/10.1038/s41380-019-0496-z
Multi-omic biomarker identification and validation for diagnosing
warzone-related post-traumatic stress
disorder. Dean, et al
https://
www.wsj.com/articles/blood-test-could-help-identify-troops-suffering-from-PTSD
16 Sept 2019
Slide15Ethnicity In Relation To Auc
UNCLASSIFIED
Ethnicity MDD
Slide16UNCLASSIFIED
Slide17AUC
= 0.80, 81% accuracy,85% sensitivity,
77% specificity).Found stable molecular signaturesCould detect the interference andcomplications of ‘biotypes’UNCLASSIFIED
Slide18DNA Methylation of Genes Regulating
Circadian Rhythm
CLOCK = Circadian Locomotor Output Cycles KAPUT
Slide19log2 (fold change)
node size (significance)
Circadian rhythm - entrainmentdecreased by addictionTelomere maintenanceLT synaptic potentiation
DNA repair/
telo
- mere maintenance
glutamatergic
synaptic transmission
Response
to drugs
MEMORY
Long-term(LT) synaptic plasticity
Human PTSD Blood DNA Methylation (Therefore, Inhibition of
t
he Function)
red nodes:
hypermethylated
genes at the promoter region
Slide20OIF/OEF Male Cohorts
Veterans (Lines 1-3):
Age/ethnicity balanced, Male subjects PTSD+SubthresholdNon-PTSDDiscovery Baseline
83
83
Discovery Follow-up
16
12
31
Validation
26
28
Validation 2
28
10
Fort
Campbell Active Duty
76
57
>2500
Active Duty:
Males
Before deployment
3 days
after
3-4
month after
Number of subjects
939 728
1167
PTSD
+: PCL >= 38,
PTSD subthreshold 28
=<
PCL<38
Non-PTSD
PCL < 28
DSM-5
Veterans
Slide21A) 28 PTSD/10 CONTROLS
(Veterans, mostly recent)From a therapeutic study at Bronx VA prior to onset of treatmentB) Fort Campbell phases 1,2,3. Pre/ x2 post deployment
Selection of 1400 samples representing ~170 PTSD or high subthreshold males, at multiple time points along with many controls for each. (FDA suggestion)C) Females Fort Campbell: 125, ~10 with high subthreshold PTSDD) Grady cohort. 800 samples. Selected by Dr. Ressler to likely have some characteristics similar to Military.~350 males, 450 femalesSubsequent Clinical Cohorts - Validation
Slide22PTSD Subtypes
Dissociative subtype and
re-experiencing/hyperaroused subtype [R Lanius, et al. Am J Psychiatry, 2010]Depressive subtype and anxiety subtype [R Chen et al, Am Acad. Neuro, 2014]Inferring subtypes from high throughput molecular data
Slide23Identification of 103 Methylated Gene Regions Associated with Clinical Features
UNCLASSIFIED
500 repeats with random removal of 5 samples each timeSelected the top 103 most-frequent candidate features
Slide24UNCLASSIFIED
Slide25Trauma-exposed Combat
Males
PTSD Negative
G1
Biotype
G2
Biotype
Symptomatically
Negative
Symptomatically
Positive
Epigenetically
similar to control
Epigenetically
distinct to control
(a)
(b)
(c)
Assign PTSD to
G1 or G2
Biotypes
Slide26UNCLASSIFIED
Slide27Severity Scales
Training
ValidationTrainingValidationCriterion D for DSM IV: Increased arousal Difficulty falling or staying asleepIrritability or outbursts of angerDifficulty concentratingHypervigilanceExaggerated startle response2+ symptoms presentMississippi Combat Scale Criterion D plus depression
Slide28G2 Biotype Has Significantly Higher Symptoms
for Veteran a
nd Active Duty MalesUNCLASSIFIEDFort Campbell Active Duty CohortOIF/OEF Veteran CohortsG2 is a hyperaroused and re-experiencing biotype Pre-deploy 3-4 month post deployment
Slide29G1/ G2 Have No Difference in MDD+/-PTSD Cohort
Slide30Biotypes Differed in Anxiety and Depressive Symptoms
Slide31G2 Biotype Has More Risk to PTSD
Slide32Top Differentially Methylated
Signaling
PathwaysAntigen Presentation PathwayOpioid SignalingNeuropathic Pain Signaling CREB Signaling Neuroinflammation SignalingDissociative subtype defensive freezing behavior
presynaptic
opioid receptors that mediate analgesic
relief
S
Harricharan
, fMRI functional connectivity of the periaqueductal gray in PTSD and its dissociative subtype, Brain
Behav
., 2016; T.
Musha
, et al. J
Pharmacol
Exp
Ther
, 1989
Slide33UNCLASSIFIED
Slide3428 multi-panel biomarkers
G1 (11) vs Control (26)
G2 (15) vs Control (26)PTSD+(26) vs Control (26)AUC0.500.890.71Sensitivity0.360.93
0.69
Specificity
0.81
0.77
0.69
Biotypes Performed Differently on Prior Diagnostic Marker
12
DNA-m
markers
G1 (11) vs Control (28)
G2 (15) vs Control (28)
PTSD+(26) vs Control (28)
AUC
0.
78
0.8
9
0.85
Sensitivity
0
.
73
0.
93
0.8
5
Specificity0.86
0.82
0.82
Differentially Methylated
in
G1
vs
Control
in
discovery,
Consistent
methylation
direction
in discovery and filter cohortsDifferentially Methylated in G2 vs Control in discovery, Consistent methylation direction in discovery and filter cohorts
Slide35UNCLASSIFIED
Next steps:
Continue evaluation of the 1300 Aptamer-identified proteomics regarding the 2 biotypes /overall panel and inflammatory mediators, CREB proteins, etc. Obtain new active duty SM samples from Beidel study ( Portsmouth Naval, Camp Lejune Hospitals & DD Eisenhower Army Medical Center) Fort Campbell phases 4-5 Lofty Aim: to be able to report with our panel ‘features’ typical of PTSD (sleep & metabolic disturbances, hyperarousal, circadian disruption, etc) BEFORE they coalesce to PTSD.
Slide36Acknowledgments
PTSD Systems Biology Consortium Leadership
Dr. Marti Jett, ST Senior/Chief Scientist, Systems Biology US Army Medical Research and Development Command (MRDC)/WRAIR, Dr. Charles Marmar, New York University (NYUMC)Dr. Frank J. Doyle III, Dean, Sch Eng & Appl Sci , Harvard University, Cambridge, MADr. Lee Hood, Institute for Systems Biology Seattle, WADr. Rachel Yehuda, Mount Sinai School of Medicine (MSSM) and Bronx VADr. Owen Wolkowitz, Synthia Mellon, University of California at San Francisco (UCSF)Dr. Kerry Ressler, McLean/Harvard University, Cambridge, MADr. Ronda Renoski MOMRP Psychological Health Portfolio ManagerCo-investigators & Study TeamRasha Hammamieh, Ph.DRuoting Yang, Ph.DAarti Gautam, Ph.DKai Wang Ph.D.Inyoul
Lee
Ph.D
Guia Guffanti
Ph.D
Kelsey
Dean, Ph.D
Duna Abu-Amara M.P.H
Janine Flory Ph.D
Anna Suessbrick Ph.D
Rohini
Bagrodia MA
Meng Qian Ph.D.
Meng Li MS
Lynn
Almli
Ph.DIouri Makotkine MDJennifer Newman Ph.D.
FUNDING: DoD, Dept Health Affairs/ CSI
Slide37UNCLASSIFIED