CTA COSR White Paper - Computer Technology Associates

kettlecatelbowcornerAI and Robotics

Nov 7, 2013 (3 years and 9 months ago)

70 views








White Paper






IN
-
THEATER
COMBAT OPERATIONS STRESS
REACTION (COSR) HEALTH RISK ASSESSMENT

AND MANAGEM
E
NT








C
C
o
o
m
m
p
p
u
u
t
t
e
e
r
r


T
T
e
e
c
c
h
h
n
n
o
o
l
l
o
o
g
g
y
y


A
A
s
s
s
s
o
o
c
c
i
i
a
a
t
t
e
e
s
s
,
,


I
I
n
n
c
c
.
.




H
H
e
e
a
a
l
l
t
t
h
h


S
S
o
o
l
l
u
u
t
t
i
i
o
o
n
n
s
s


D
D
i
i
v
v
i
i
s
s
i
i
o
o
n
n













Stanford Medical Informatics





CTA Proprietary


ii


Table of Contents

EXECUTIVE SUMMARY

................................
................................
................................

1

Analytical Foundation: Develop In
-
theater Anticipatory COSR Health Risk
Manage
ment Model.

................................
................................
................................
...

1

Informatics Foundation: Develop Rapid Multivariate Data Fusion Capability for
In
-
Theater Health Risk Management Decision Support.

................................
.........

2

OIF MENTAL HEALTH OVERVIEW

................................
................................
...............

3

Current Challenges

................................
................................
................................
....

3

COSR Health Risk Management Objectives

................................
.............................

3

Existing COSR Health Risk Surveillance and Assessment Capabilities

...............

3

COSR Resilience Experience

................................
................................
....................

4

Capability Gap

................................
................................
................................
............

4

ANALYTICAL FOUNDATION: MULTIVARIATE COSR RISK ASSESSMENT

.............

5

Biological Risk Factors

................................
................................
..............................

5

Biometric Data Augmentation

................................
................................
...........................

5

Genetic

................................
................................
................................
................................

6

Candidate Genes for COSR Risk Resil
ience Assessment

................................
..............

6

Genes Influencing the Neurobiology of Stress Response and PTSD

..........................

6

Genes Identified With Elevated Risk for Majo
r Depression in Populations Exposed
To Extreme Stressors and Implicated In the Neurobiology of Depression and
Antidepressant Response

................................
................................
..............................

7

Functional Brain Chemistry

................................
................................
...............................

7

Psychological Risk Factors

................................
................................
.......................

8

COSR Health Risk Resilience Continuum

................................
................................
........

8

Psychometric Resilienc
e Assessment

................................
................................
.............

8

Functional Assessment

................................
................................
................................
.....

9

Historical/ Demographic/Environmental Risk Factors

................................
............

9

Historical/Demographic Pre
-
Traumatic Risk Factor Data in Military Populations

.........

9

Sources for Combat Stress Risk Factor Data

................................
................................
..

9

INFORMATICS FOUNDATION: ONTOLOGY BASED INFORMATION
AGGREGATION, BAYESIAN NETWORK FUSION

................................
.....................

10

Informatics Infrastructure Concept

................................
................................
.........

10

Ontological Foundations

................................
................................
.........................

10

Automated Surveillance and Inferencing

................................
...............................

11

COSR HEALTH RISK ASSESSMENT POPUL
ATION STUDY CONCEPT

.................

11

Null Hypothesis

................................
................................
................................
........

11

COSR RESEARCH STUDY TEAM

................................
................................
...............

12

REFERENCES

................................
................................
................................
..............

13



1


CTA Proprietary

EXECUTIVE SUMMARY

The Medical Situational Awareness in the Theater (MSAT) initia
tive by OSD
-
HA is directed at
the

unmet need for timely, actionable health risk information for operational decision
-
makin
g by
military field
commanders that minimize

troop exposure to preventable, adverse consequences of
combat. Within the broad health
-
related mission areas relevant to the MSAT objectives (e.g.
medical surveillance of disease and non
-
battle injuries (DNBI),

physical and psychological battle
trauma, medical logistics), the mission area focus of this proposal is the in
-
theater management
of Combat Operations Stress Reaction (COSR) and the related psychological consequences of
battle trauma. The specific objec
tive of this proposal is the development of the analytical and
informatics foundational capabilities that will enable the accurate and timely determination of
emerging COSR health risks and threats to functional capacity of combat populations prior to,
dur
ing, and after deployment in theater. It is expected that these infrastructure capabilities will
serve other MSAT mission areas (e.g. DNBI) as well.

Recent studies indicate that 16 to 19% of soldiers involved in combat operations in Iraq may be
at elevate
d risk for developing serious mental health complications. Recent reports indicate that
as of February 2005, over 12,000 veterans of OEF and OIF have been treated for PTSD. Given
the magnitude of the effected soldier population, improvement in current capa
bility for detection,
prevention and intervention has potential to yield significant benefits for sustaining combat
operations, preventing psychiatric complications, and red
ucing long
-
term disease burden.

Existing VA/DoD practice guidelines emphasize preve
ntion of adverse COSR consequences
with the simultaneous purpose of rapid return to duty. To achieve these objectives, military
commanders need just
-
in
-
time, comprehensive, automated health information decision support
tools for rapid fusion of data from h
ighly diverse sources that enable the early assessment and
determination of soldier subpopulations at significant elevated risk for compromised mission
function and serious mental health complications. A dual
-
focus
analytical and informatics
infrastructure

solution is envisioned
:

Analytical Foundation: Develop
I
n
-
theater
A
nticipatory COSR
H
ealth
R
isk
M
anagement
M
odel.

Current military COSR health risk assessment procedures rely on pre or post
-
deployment,

single

point
-
in
-
time, self
-
administered, subjective
screening protocols for identifying psychiatric
disorders after symptom and behavioral man
ife
stations reach diagnostic threshold criteria. Th
ose
capabilities do not

address the dynamic nature of in
-
theater operations, or the need for real
-
time
medical situ
ational awareness to support field commanders in health risk management decision
-
making. The proposed solution envisions d
e
veloping a new, unprecedented best practice
paradigm, offering potential for pre
-

clinical detection of potential mental health disor
ders
upstream in the process of development, before expression of typical symptoms and behaviors
associated with the condition are apparent. This novel approach would expand the current COSR
assessment protocols to encompass a broad spectrum of interrelati
ng, health risk data points that
are continuously monitored and integrated throughout the pre/in
-
theater/post deployment time
continuum. In this comprehensive, anticipatory risk management model, evidence based health
risk data (
including:

genetic and func
tional brain chemistry biomarkers, clinical and laboratory
data, predisposing mental health risk factors, psychometric and functional assessments, health
history and medical/personnel records) are fused with continuous stream, in
-
theater health risk
data
(including: functional brain chemistry biomarkers, resting heart rate, medical
records/clinical/laboratory, routine psychological screening instruments) and situational
assessment data (including: combat action and casualty reports). Applying technologies

with


CTA Proprietary


2

dynamic causal inferencing capability such as Bayesian Networks will enable linkage of these
multivariate health risk determinants before, during and after combat trauma exposure, enabling
accurate, probabilistic COSR health risk determination.

Infor
matics Foundation: Develop
R
apid
M
ultivariate
D
ata
F
usion
C
apability for
I
n
-
T
heater

H
ealth
R
isk
M
anagement
D
ecision
S
upport.

Delivering just
-
in
-
time, actionable health risk management decision support information to field
commanders requires automated coll
ection, rapid fusion and multivariate analysis of COSR
health risk data extracted from multiple, heterogeneous information sources. The proposed
solution identifies specific DoD “horizontal fusion”, “syndrome surveillance”, commercial
“semantic web” and ar
tificial intelligence technologies for capturing, synthesizing and
interpreting health risk data associated with dynamically changing battlefield variables. The
proposed solution combines such technologies with existing, disparate sources of military
oper
ations data to enable automated data extraction from diverse in
-
theater information sources
and near real
-
time fusion with an individual soldiers’ aggregate health risk profile to deliver real
-
time decision support for effective COSR health risk management
.

To develop these foundational capabilities, an epidemiologic, three
-
phase prospective population
level research endeavor is envisioned. The proposed study would continuously monitor, collect
and analyze data obtained from a statistically significant coho
rt sample of combat soldiers at risk
for adverse COSR outcome, through the full pre/in
-
theater/post
-
deployment continuum. The
entire study cohort must be followed over time to capture and correlate variables associated with
battlefield events (i.e. COSR re
sponse to various forms of combat exposure) and the spectrum of
mental health outcomes for those who experienced the event.



CTA Proprietary


3

OIF
MENTAL HEALTH
OVERVIEW

Current Challenges

Recent reports indicate that the surreptitious threat from suicide bombers and snipe
rs in Iraq is
even more stressful than open combat. Through the end of April, 1,118 Army men and women
had been evacuated from Iraq for psychiatric reasons, according to official statistics. Through
February, according to the Department of Veterans Affairs
, 12,020 veterans of Iraq and
Afghanistan had been treated for post
-
traumatic stress disorder [N.Y. Times 6 June 2005].

Recent military

studies
[Hoge, 2004
]
regarding the prevalence of mental health problems
associated with OIF COSR
indicate:



9
6
% of
more
than 25,000

thousand soldiers surveyed reported experiencing
combat of
such
severity/intensity and/or repetitiveness (e.g. being ambushed, multiple firefights, hand
-
to
-
hand
combat, etc.) that they perceived themselves
as

being in immediate danger of seriou
s injury or
death
; and over half (55%) reported experiencing that perception

“many times”
;



16
-
19% of infantry
s
oldiers or
m
arines screened positive for a mental health problem when
surveyed 3 to 6 months post
-
deployment Iraq
;



The largest increase in mental

health problems post
-
deployment compared to pre
-
deployment
baseline
was for posttraumatic stress
disorder (PTSD) (12
-
15% vs. 5%)
;




A
lcohol misuse

was twice as prevalent in soldiers with PTSD (50+ %) than without (25+);



O
ne
-
third of
service members
wit
h mental health problems receive any professional
help
;



A majority of soldiers
with mental health problems perceive
multiple barriers to receiving care,
including fear of stigmatization.


COSR Health Risk Management Objectives

VA/DoD Clinical Practice Guid
elines define the following in
-
theater military objectives for
Combat Operations Stress Reaction (COSR) management [The Iraq Clinician Guide, NCPTSD]:



Prevent exacerbation or mitigate symptoms of acute stress;



Prevent development of traumatic stress comp
lications
, including

acute stress disorder
(
ASD
)
,
posttraumatic stress disorder
(
PTSD
)
, major depression
(
MD
)
, anxiety disorders, and substance
abuse disorders;



Keep service member (SM) with their unit and prevent unnecessary medical evacuation;



Return
s
ervice member
to duty as soon as possible;



Maintain and enhance unit capabilities.

G
iven widespread, repetitive exposure to intense combat stress experienced by large sub
-
populations of active military, th
is proposal
addresses
the application of highly

automated “in
-
theater” COSR health risk data collection and analysis tools in support of these objectives. Our
premise is that continuous in theater surveillance and fusion of key risk factors will
provide
military commanders
and clinicians
with
just
-
in
-
time
,
actionable
“mental health situational
awareness” information
for decision support in balancing priorities of

changing combat mission
requirements with preservation of long
-
term mental health and well
-
being of
warfighters
.

Existing
COSR Health Risk
S
urveillance and
Assessment

Capabilities

Current military

surveillance and
assessment protocols for COSR health risk focus on self
-
administered pre and post
-
deployment screening protocols for identifying psychiatric disorders,
with optimal results obtained
from surveys taken months after exposure
[Wright, 2005]
. Reports
of mounting psychological casualties in soldiers returning from the Iraq War have fueled
considerations for upstream, in
-
theater surveillance and real
-
time assessment focused on earlier


CTA Proprietary


4

detec
tion of risk for traumatic psychiatric injury, and in particular for the sub
-
clinical/“stealth”
population of soldiers not exhibiting overt, clear cut signs of mental disorder
[Hoge, 2004)]
.
This need
for in theater surveillance
is highlighted
by finding
in these studies which demonstrate
that greater combat exposure is significantly correlated with increased prevalence of serious
mental disorders; adverse mental health impact is related to combat stressor category type; and
potential adverse effects of co
mbat stress are cumulative and compounded over time,
exemplified by
a

linear relationship between number of experienced firefights and PTSD
prevalence

[Hoge, 200
4
]
.

Although there are relatively few evaluations of existing military psychiatric screening pr
otocols,
those studies have produced equivocal evidence for efficacy, with variable, suboptimal rates of
false positives and negatives reported
[Rona, 2005]
. For example, a recent study focused on
identifying PTSD in soldiers redeploying to Iraq using stan
dardized
VA/DoD

criteria (PTSD
Check List or PCL and DD FORM 2796), identified an unexpectedly low percentage of soldiers
meeting full diagnostic criteria for PTSD who were subsequently referred for follow
-
up care.
The study also reports that although crit
eri
a were effective in identifying

relatively severe cases
of PTSD, they were ineffective for identifying the sub
-
clinical soldier population without
manifest symptoms, or mild to moderate symptoms, that might have benefited from referral for
more in
-
depth

assessment and indicated preventive intervention
[Bliese, 2004
]
.

Those findings are the subject for ongoing research by the USAMRU
-
E to develop a modified
primary screening tool

including

five to ten items selected from a combination of the PTSD
Checklist

(PCL) and DD FORM 2796 that has excellent predictive properties
[Bliese, 2004]
.
That research effort is also investigating impact of PTSD risk factors on screening methodology
and results.

COSR Resilience

Experience

Iraq war COSR data support an assumpti
on that soldiers exposed to combat experience
composite response patterns of biological, psychological, behavioral/functional adaptation.
Based on current reports
,
80 to 85%

of that population exhibit COSR resilience, with preserved
or even superior functi
on, and return to baseline without mental health complications. A smaller
subset of combat soldiers fails to exhibit COSR resilience. This group experiences persistent
stress adaptation that does not return to baseline, potentially expressed near term as i
mpaired in
-
theater function and performance of duty, and longer term, as serious, debilitating mental
disorders.

Capability Gap

Based on those observations and assumptions there is an urgent unmet need to enhance
the
military
mental health risk surveillan
ce and
assessment capability for
an
accurate, timely
determination of resilient and non
-
resilient populations through the full deployment continuum.
This capability is an absolute imperative for all in
-
theater forward/proximal Echelons of Care (I,
II, and
III)
[The Iraq Clinical Guide, NCPTSD]
, where access to just
-
in
-
time, actionable,
decision support information at point
-
of
-
contact enables real
-
time, COSR risk assessment, early
problem recognition, triage, restorative intervention, return to duty (RTD), a
nd prevention of
serious psychological complications and disability.

This proposal for collecting, aggregating and analyzing multiple data sources for a cohort of
combat soldiers through the pre
-
deployment/ in
-
theater/post deployment cycle will establish
the
requisite analytical models and informatics infrastructure for building a novel approach for


CTA Proprietary


5

assessment of individual combat soldier COSR health risk level
s
. Deployment of such a
capability would facilitate early problem recognition, triage, restorati
ve intervention, return to
duty (RTD), and potentially result in the prevention of serious psychological complications and
disability for thousands of active military.


ANALYTICAL FOUNDATION
:
MULTIVARIATE
COSR
RISK
ASSESSMENT

A
conceptual
risk assessment
model

is envisioned recognizing that the continuum between health
and disease is evolving, dynamic and continually redefining itself in response to a broad array of
predisposing and dynamically changing situational variables. To effectively address that
co
mplexity, the proposed solution expands the current single point
-
in
-
time, post
-
deployment,
psychometric assessment approach to encompass a spectrum of interrelated, evidence
-
based
biological, environmental and psychological

risk factors
,

designed to detect

resilient and non
-
resilient sub
-
populations across the full deployment cycle continuum.
It is well established that
the
fusion of
data from
multiple, heterogeneous information sources
taken from differing
perspectives
related to an event can result in enh
anced detection, recognition
of risk
and
assessment of underlying caus
ality.


T
he proposed solution
leverages
a
growing scientific evidence

base

from the PTSD research and
clinical communities
,
including

genetic and functional

brain chemistry

biomarkers,
p
redisposing
demographic
risk factors, psychological and functional assessment
factors
. The envisioned
COSR multivariate risk assessment model integrates that database with continuous stream

data
inputs from
a

changing
in
-
theater

military operations data
bas
e

of related information
,
including
brain chemistry biomarkers,
health history and medical records, clinical and laboratory data,
combat action and casualty reports
,
peritraumatic
psychometric assessments
) across the full
deployment cycle time continuum. T
ransforming those diverse information sources into
actionable information requires an advanced, multivariate information technology solution with
“GPS”
-
like capacity for
accessing and
fusing multiple, intersecting data
-
point coordinates to
accurately pinpo
int
emerging
COSR health risk
s

in real
-
time, at point
-
of
-
contact.

Biological
Risk
Factors

Biometric Data Augmentation

Over the past decade consensus recognition has developed for the genetic and biologic basis of
mental health disorders, including majo
r depression, bipolar disorder and schizophrenia. This
recognition has resulted in legal precedent and legislative mandates for parity in health insurance
coverage for mental illness.

Review of current military protocols for COSR health risk
surveillance a
nd
assessment reveals
no systematic application of an emerging
biometric
evidence base on genetic and b
iologic

studies demonstrating significant associations between
genetic variables and their influence on
quantifiable
,

adaptive changes in functional brai
n chemistry in response to stress.

Application of this evidence base
would
create a

new, unprecedented

best practice

paradigm,
offer
ing
potential for detection of potential mental health disorders
upstream
in the process of
development, pre
-
clinically
, be
fore expression of
typical
symptoms and behaviors associated
with the condition are apparent.
This early detection capability would provide COSR health risk
management decision support and facilitate proactive preventive intervention. It would also

address

other capability gaps of currently employed screening protocols by
minimiz
ing

both


CTA Proprietary


6

false positives
,
including malingering
,
and negatives, and
improving
assessment results
by
reducing

variation introduced through

subjectivity
and
bias variation effects.

A biometrically augmented “litmus test” paradigm is envisioned, enabling identification and
classification of combat exposed soldier populations into three major population subsets: highly
resilient with high likelihood for superior ongoing function withou
t psychiatric complications;
resilient with high probability for satisfactory ongoing function without psychiatric
complications; or low/non
-
resilient with high probability for compromised ongoing function and
development of psychiatric complications.

Rel
evant knowledge domains within
the biometric

evidence base are briefly outlined below.

Genetic

The Vietnam Era Twin (VET) Registry, created from military records, consists of male
-
male
twin pairs who served in the military during the Vietnam Era. Analysis
of the registry
demonstrated genetic influences on all PTSD symptoms, after adjusting for differences in
combat exposure
[True, 1993]
. Similar findings are reported in a non
-
veteran volunteer
community sample of male and female twins
[Stein, 2002]
. Furth
er studies on the VET Registry
have shown shared genetic influences on PTSD and other mental disorders, including alcohol
and drug dependence
[McLeod, 2001]
, anxiety and panic disorder symptoms
[Chantarujikapong,
2001]
, and major depression
[Koenen, 2003]
.


The most recent evidence for genetic influence on PTSD comes from a recent study of specific
blood cell type (mononuclear) gene expression profiles for individuals seen in the emergency
room shortly after a traumatic event and followed
-
up one and four mo
nths later. The study
found that gene expression signatures differentiated between individuals who would go on to
develop PTSD and those who would not. The authors conclude those findings offer promise for
developing a predictive test to identify survivor
s who are at higher risk of developing PTSD after
a traumatic event and therefore more likely to benefit from preventive intervention
[Segman,
2005]
.

Candidate Genes for COSR Risk Resilience
Assessment

Current evidence for understanding the neurobiology of

stress and the development of post
-
trauma
psychopathology
, identifies a number of candidate genes with variations in multiple
DNA nucleotide base pair sequences (i.e. polymorphism), a single DNA nucleotide base pair
sequence (i.e. SNP), or variant alleles

(i.e. pairs of genes located at the same position on both
members of a chromosome pair) that may influence COSR health risk resilience.

Genes
Influencing the Neurobiology of Stress Response and
PTSD



Catechol
-
O
-
Methyltransferase

(COMT
)
: COMT Val158Met is a

common genetic polymorphism
that influences enzymatic metabolism of norepinephrine and dopamine. The Met158 allele of the
pair modulates lowered enzyme activity in association with lower stress resilience and elevated
risk for anxiety related diagnoses
[
Olsson, 2005]
.



Alpha2C Adrenergic Receptor (A2CAR)
: Variation in the A2CAR gene is a candidate risk factor
for the observed increase in noradrenergic regulation associated with PTSD. The alpha
-
2C
receptor is a terminal receptor for noradrenergic neurons
in the brain and body.
Polymorphism at
the A2CAR locus substantially alters the level of expression of this receptor
[Small, 2004]
.



Neuropeptide Y (NPY) gene
: NPY is co
-
localized with norepinephrine, among other
neurotransmitters, and released in associat
ion with burst firing of noradrenergic neurons.
Through its receptors (NPY1, NPY2), NPY may decrease release of norepinephrine and
acetylcholine in the hypothalamus, medulla, and sympathetic nervous system
[Tsuda, 1990]
. A
Leu7Pro SNP in the NPY gene that

may influence circulating levels of NPY has been described


CTA Proprietary


7

infrequently (2%) in the general population, but with more than twice this rate in veterans with
PTSD or alcoholism (5%
-
7%)
[Lappalainen, 1995]
.

Genes
Identified With Elevated Risk for Major Depre
ssion in Populations Exposed To Extreme
Stressors and Implicated In the Neurobiology of Depression and Antidepressant Response



Serotonin Transporter Gene Promoter (
SLC6A4
)
: There are two common variant alleles, a short
form (s) and long form (l). The shor
t allele appears to amplify stress adaptation response, in part
by increasing reactivity of the amygdala, an important brain structure that plays a central role in
activating the hypothalamic
-
pituitary
-
adrenal axis response to stress
(A. R. Hariri et al., 2002)

[Hariri, 2002]
. A landmark study found that the (s) allele increases risk for depressio
n in abused
children
[Caspi, 2003]
.



Neurotrophic Factor (BDNF)
: The principal polymorphism studied is a SNP in the DNA
sequence coding region (V66M) that reduces the release and impact of BDNF on the
hippocampus
[Chen, 2004]
. The hippocampus plays a promi
nent role in stress response,
particularly behavioral inhibition, contextual conditioning, and inhibiting activation of the
hypothalamic
-
pituitary
-
adrenal axis. This polymorphism is associated with impaired hippocampal
performance of memory tasks and reduc
ed structural volume
[Egan, 2003; Pezawas, 2004]
. In
addition, some studies show that the

met allele of the BDNF gene is associated with depression or
antidepressant response in children and in adults
[Strauss, 2004; Tsai, 2003]
.



FKBP5: V
ariation in this g
ene has been associated with greater recurrence of depressive episodes
and rapid response to anti
-
depressant treatment in two independent samples. Authors cite the
possible role of FKBP5 in regulating and increasing hypothalamic
-
pituitary
-
adrenal axis tha
t may
result in more rapid onset of stress hormone hyperactivity after stressful life events
[Binder,
2004]
.


Functional
Brain
Chemistry

The genetic evidence base correlates with a neurobiolog
ic

evidence base demonstrating
significant relationships betw
een stress exposure, measurable/quantifiable changes in brain
neurochemistry, and their impact on stress resilience and risk for developing PTSD and major
depression. That evidence suggests that monitoring and tracking changes in the levels of 3
important
central nervous system biomarkers and a specific, associated physical finding over
time (i.e. Cortisol, a neurohormone; Norepinephrine, a neurotransmitter in association with
resting heart rate; and Neuropeptide Y, a common central nervous system peptide),

may yield a
promising new opportunity for detecting sentinel patterns of changing brain function and
chemistry that will enable distinction between resilient and non
-
resilien
t combat soldier
populations.



Cortisol
: Exposure to traumatic stress mobilizes an

adaptive neurochemical response cascade that
supports assessment of danger, and organizing and executing proportional behavioral response.
The stress response is ultimately terminated by release of cortisol from the adrenal gland. Data
from prospective st
udies suggest that individuals with PTSD show lower than expected
elevation in salivary cortisol levels after stress exposure
[Yehuda, 2002]
. Those data coupled with
evidence from other studies with active duty police officers demonstrating a relationshi
p between
lower baseline levels of cortisol observed in association with more severe PTSD symptoms,
indicate that suppressed cortisol response after traumatic stress exposure may constitute a
significant risk factor and/or a sentinel proxy measure for PTSD

[Neylan, 2005]
.

Evidence for the converse hypothesis, i.e. robust elevation in cortisol response to stress as a proxy
measure for resilience, is described in a recent study of U.S army soldiers undergoing military
survival training. Study results demonst
rate that salivary and serum cortisol measures increased
proportionally to stress levels and were highest during the captivity phase of training, which was
also assessed as most stressful through subjective measurement. Cortisol measures remained
significa
ntly elevated at recovery
[Morgan, 2000]
.



CTA Proprietary


8

Other studies offer evidence suggesting that prolonged, elevated cortisol release is associated
with major depression
[Wong, 2000]
.




Norepinephrine and resting heart rate
: There is evidence that extreme stress in
duces persistent
elevation in release of norepiniphrine from the brainstem (i.e. locus coeruleus). Sustained
elevation in norepinephrine levels can be expressed as symptoms associated with PTSD, such as
chronic anxiety, fear, and intrusive memories. Associ
ated evidence that intensity of biological
stress response to a traumatic event is predictive of PTSD development is offered in study
showing that trauma survivors who met criteria for PTSD four months after trauma exhibited
significantly higher resting he
art rate (12 beats per minute) than controls
[Shalev, 1998]
. There is
evidence of increased noradrenergic response in association with both major depression and
PTSD
[Wong, 2000; Geracioti, 2001]
. Changes in brain levels of norepinephrine can be assessed
through salivary measurement of its major metabolite, MHPG (3
-
meyhoxy
-
4
-
hydroxy
-
phenylglycol). Strong correlation between increase in MHPG levels and history of childhood
trauma, shown to be a significant risk factor for PTSD in military populations
[Brewi
n, 2000]
, is
reported in a study of police academy recruits with history of childhood trauma vs. controls
shown a video of real
-
life officers exposed to highly stressful situations. Only the childhood
trauma history study cohort showed increases in salivar
y MHPG, while both cohorts
demonstrated robust increases in salivary cortisol levels
[Neylan, 2005]
.




Neuropeptide Y

(NPY): NPY, a 36 amino acid peptide, is one of the most abundantly distributed
peptides in the human brain. There is emerging evidence that

it plays a central role in regulating
expression of anxiety, fear and depression. Preliminary studies in special operations soldiers
undergoing extreme training stress demonstrate significant correlation between high NPY levels
and superior performance
[M
organ, 2000]
. In contrast, lower NPY levels have been reported in
association with PTSD
[Rasmusen, 2000]
.

Psychological
Risk
Factors

COSR Health Risk Resilience Continuum

COSR risk expression may proceed along a continuum, from acute stress reaction (ASR),

to
acute stress disorder (ASD), to PTSD. Because the diagnosis category of ASD was added
relatively recently to standardized DSM
-
IV diagnostic criteria, there are relatively few measures
for validating measures of acute stress against those criteria. At p
resent, the best available
instruments for diagnosing and quantifying ASD severity are pair
-
related measures, the Acute
Stress Disorder Interview (ASDI) and the Acute Stress Disorder Scale (ASDS)
[Bryant, 2000]
.
The ASDI is a clinician administered interv
iew covering specified criteria in simple yes or no
format to determine ASD diagnosis. The ASDS is a self
-
report measure for ASD symptoms
found to correctly classify 91% of those subsequently diagnosed with PTSD and 93% of those
who did not have PTSD.

COSR

health risk expression may also include other mental disorders, principally major
depression and/or generalized anxiety disorder, alone or concomitantly with PTSD. Well
-
validated self
-
report measures of anxiety and depression used in research and clinical

practice
include the Beck Depression Inventory
[Beck, 1961]

and the state
-
anxiety portion of the State
-
Trait Anxiety Inventory
[Spielberger, 1970]
.

Psychometric Resilience Assessment

The Connor
-

Davidson Resilience Scale (CD
-
RISC) measures and quantifies
resilience. The
scale comprises 25 items, each rated on a five
-
point (0 to 4) scale, with good internal consistency
and test
-
retest reliability. The instrument demonstrates linkage between resilience and health


CTA Proprietary


9

status, so that individuals with mental illne
ss exhibit lower levels of resilience than the general
population. In validation studies, PTSD was the psychiatric condition with lowest score (50.3),
followed by major depression (58.4), generalized anxiety disorder (62.4), and generalized U.S
population
samples (80.4). Studies also revealed that resilience is modifiable, can improve with
pharmacotherapy, and higher levels of resilience correlate with greater levels of global
improvement in psychiatric disorder
[Connor, 2003]
. Pre/post
-
deployment CD
-
RISC s
core data
will augment multivariate resilience assessment.

Functional Assessment

Va/Dod Practice Guidelines specify performing brief assessment of function based on general
appearance and behavior to evaluate: objective and subjective impairment in funct
ion; baseline
pre
-
deployment level of function vs. current level of function; and family relationship
functioning
, substance abuse, etc.
The practice guidelines also reference standardized
instruments for assessing global function, including the DSM IV Gl
obal Assessment of Function
Scale (GAF) and the RAND Corp. SF
-
36. Anecdotal communications from psychiatrists
deployed in
-
theater report strong correlation between high
-
level pre
-
deployment functioning,
performance in combat, and COSR health risk resilienc
e
[The Iraq Clinical Guide, NCPTSD]
.

Historical/ Demographic/Environmental Risk Factors

Historical/Demographic Pre
-
Traumatic Risk Factor Data in Military Populations

The evidence base offers support for including risk factor variables in COSR health risk
r
esilience assessment. Findings from a meta
-
analysis of risk factors, comparing military and non
-
military populations of adults exposed to trauma, revealed significant differences in effect size
for risk factors on likelihood of developing PTSD [Brewin, 200
0]. Childhood adversity, trauma
severity, lack of education and social support all demonstrated stronger effect sizes in military
compared with civilian populations. Ethnicity was found to be a weak predictor for both civilian
and military populations; and

the gender effect observed in civilian populations (i.e. PTSD
prevalence for women twice as high for men) was not observed in military populations. The
study also found that situational or “peritraumatic” risk factor variables operating during or after
tr
auma exposure, such as trauma severity, lack of social support and additional life
-
stressors,
showed stronger PTSD risk effects than historical (pre
-
traumatic) factors. Sources of historical
risk factor data include personnel files and medical records.

Sou
rces for Combat Stress Risk Factor Data

Major sources for combat stress risk factor data include after action combat, casualty, and
medical reports. For example, the previously referenced study under Problem Scope identifies 18
separate categories of stres
sful combat experiences, any one of or combination of which (e.g.
being fired upon, becoming a prisoner of war, sustaining an injury, or witnessing serious injury
or death) may be associated with exposure variables including duration, severity and intensit
y
that impact stress resilience and associated risk of adverse COSR mental health outcomes
[Wright, 2005]. It is envisioned that typically generated after action reports and media related
reports describing exposure characteristics will supplement subjecti
ve stress characterizations
recorded in survey data and provide opportunities to study resilient and non
-
resilient sub
-
populations exposed to common combat stressors experienced in the Iraq conflict.




CTA Proprietary


10

IN
FORMATI
CS
FOUNDATION
:
ONTOLOGY BASED INFORMATION

AGG
REGATION, BAYESIAN NETWORK
FUSION

Informatics Infrastructure Concept

Because a

complex constellation of interrelated variables underlies thorough understanding of
COSR health risk assessment
,
the previously mentioned

epidemiologic,
3
-
phase, prospective
obs
ervational population study of combat troops in Iraq is
envisioned to create the requisite
database for developing accurate risk assessment capability.

To our knowledge, no investigation
to date has utilized information fusion that enables comprehensive in
tegration, correlation and
pattern analysis of all
the previously referenced
variables over time, across the full deployment
continuum.

The proposed
information
technology solution

applies advanced “semantic web” technology for
integrating, and correlating

diverse, heterogeneous biomedical and associated trauma data
extracted from structured and unstructured information sources. Structured information sources
may include biometric neurochemical and genetic biomarker assessments, psychometric
evaluation, an
d medical/personnel records extracted from emerging DoD systems such as
DOEHRS, DMSS, SAMS,

ICDB,
CHCS2
-
T, etc. Unstructured information sources include non
-
classified information in combat action reports (e.g. objective documentation detailing type,
sever
ity and duration of stress exposure, documented observations of impaired function and
performance of duty
, dissociation, etc.
) and casualty reports (e.g. types/severity prevalence of
injuries/fatalities), news media reports/press releases, publications by
the research community,
and spontaneous communications such as e
-
mail and other relevant sources.

Ontological Foundations

Ontologies are the foundation building blocks required for semantic linkage of heterogeneous
data sources. They organize data sharin
g common structural and conceptual properties into
discrete, organized “universes” with sets of domain languages and interrelationships that can be
understood by computers and used to support intelligent agent software performing automated
data access, ext
raction, association, and correlation. They are currently being evaluated by the
military for applications in higher levels of intelligence information f
usion in Command and
Control
[Boury
-
Brisset, 2003]
, and are employed in a range of biomedical research
applications.
We are unaware of similar efforts in the mental health domain, and in particular in domains/sub
-
domains related to PTSD (e.g. trauma classes/types/attributes, PTSD indications/clinical
guidelines/treatments, evaluation criteria, resilience/r
isk factors, clinical/laboratory biomarker
data, etc.).

Once vetted or “curated” by domain expertise and clinical experts, concepts embedded in
ontologies can be used to enhance and annotate metadata extracted from structured and
unstructured information

sources, thereby supplying requisite “context” and unifying structure
for developing meaningful associations and relevant information from diverse
,

multi
-
domain
sources. For example, a field commander
(or his intelligent agent)
could access the COSR heal
th
risk resilience ontology database to answer questions such as: “my combat platoon has engaged
in 5 firefights within the past month; 20% of the men are showing signs of fatigue, including
trouble sleeping, irritability and hypervigilence; half of those
have depressed cortisol and
elevated MHPG salivary levels. Based on that situational and biometric risk factor profile,
provide me with aggregate COSR health risk resilience assessments (incorporating all
multivariate risk information from supporting ontol
ogies) that provide each of the identified


CTA Proprietary


11

soldier’s probable risk for compromised function in subsequent combat missions and/or
development of
serious imminent or longer term
psychiatric complications.


The envisioned PTSD ontology will be highly sharable

(using open source tools (e.g. SMI
Protégé) and standard representation (OWL)), reusable in support of ongoing research and
clinical studies by the biomedical community, and evolvable as new relevant research results
become available. Finally, ontologie
s can guide software agent “reasoning” in performing
proactive information retrievals and data extractions to meet dynamically changing surveillance,
clinical care (e.g. computerized “reminders”) and research objectives [Aisen, 2004].

Automated Surveilla
nce and Inferencing

Answering this critical
risk management
decision support question requires capacity for
timely
collection and normalization of pre
-
diagnostic indications and risk factors that are coherently
integrated via automated i
nferencing, enabled

through intelligent agent software,
thereby
incorporating
prior knowledge into statistical risk probability calculations reflecting instant,
newly introduced data.

Knowledge
-
based systems for real
-
time epidemic surveillance (e.g.
Biological Spatio
-
Tempor
al Outbreak Reasoning Module
BioSTORM) provide a model for such
collection, integration and analysis of syndromic data extracted from highly diverse data sources
[Buckeridge, 2002]
.

Given the complex requirements of modern surveillance systems, such
syste
ms cannot rely on a small number of hand
-
tuned analytic methods for data analysis. A
variety of methods (e.g., forecasting, change detection, evidence combination)
may be

required
to process large volumes of data, to identify weak signals, to analyze multi
ple indicators, and to
account for
uncertain temporal and
spatial structure. Moreover,
combining results from these
different methods in potentially complex configurations
may be required
to
achieve high
confidence fusion results [Mahajani, 2003]. The BioS
TORM ontological foundation provides the
required flexibility
for research in heterogeneous evidence integration algorithms and strategies.

Dynamic
Bayesian Networks
(DBNs)
are an example of a class of
automated
inferencing tools
that will be evaluated fo
r applications in the proposed scope of work.
DBNs
are currently
employed in
a broad range of medical and
military risk management activity such as
antiterrorism and enemy course of action prediction
[
Hudson,

2001; Beinlich, 1989; Pearl, 1988).
DBNs provi
de

probabilistic extensions to mental health risk factor ontologies
that
can
deliver

dynamic, multivariate risk probability assessment

profiling

capability for each member of the
study population.


COSR HEALTH RISK
ASSESSMENT
POPULATION
STUDY

CONCEPT

Null

Hypothesis

The null hypothesis for the proposed study is designed to validate the following null hypothesis
assumptions.



In pre
-
deployment phase, the study population will demonstrate baseline set points within
anticipated range in quantitative assessmen
ts of brain function biomarker proxy measures for
combat stress adaptation.



In deployment phase, the study population will demonstrate a range of combat stress adaptation
in brain function biomarker proxy measures. During deployment, an estimated 80 to 8
5% of the
study population will demonstrate resilience, returning to pre
-
deployment baseline set point
during a yet to be determined time frame (hours/days/weeks) reflecting the severity and duration


CTA Proprietary


12

of the exposure. This biomarker response pattern will co
nstitute a reliable, valid biometric
profiling component for determining robust COSR resilience.



In deployment and post
-
deployment phases, an at
-
risk subpopulation, estimated at 15 to 20% of
the study population, will demonstrate persistent change in brain

function biomarker proxy
measures. This biomarker response pattern will constitute a reliable, valid biometric profiling
component for determining elevated COSR health risk.



In all three study phases, the resilient population will demonstrate strong assoc
iation with the
presence of a constellation and cluster patterns of associated variables, including screening,
psychometric, risk factor, functional and behavioral assessments. Coupled with biometric profile
information, this constellation and pattern anal
ysis of associated variables will constitute a
reliable, valid composite profile for robust COSR resilience.



In all three phases the at
-

risk study population will demonstrate strong association with the
presence of a specific constellation and cluster pat
tern of associated variables, including
screening, psychometric, risk factor, functional and behavioral assessments. Coupled with
biometric profile information, this constellation and pattern analysis of associated variables will
constitute a reliable, val
id composite profile for elevated COSR health risk.



During deployment and post
-
deployment phases, the resilient population will demonstrate
negative correlation with incidence and prevalence of PTSD, MD, and/or Generalized Anxiety
Disorder (GAD). Contrasti
ngly, the at
-
risk subpopulation will demonstrate positive correlation
with incidence and prevalence of PTSD, MD, and/or GAD.


COSR

RESEARCH

COLLABORATORS

Computer Technology Associates (CTA) carefully selected key researchers from Columbia
University, the
Harvard School of Public Health, and Stanford Medical Informatics to create an
expertly qualified study team.

Under contract to the Military Health Systems organization of the DoD, CTA currently performs
rigorous requirements engineering analysis in suppor
t of new medical informatics systems for
use in military operations worldwide. CTA is also currently engaged in the application of
ontology
-
directed fusion and intelligent agent applications in military/intelligence decision
support systems. For example,
as a part of APL’s “Global Net
-
Centric Surveillance and
Targeting (GNCST) effort, sponsored by the National Geospatial Intelligence Agency (NGA),
CTA is responsible for researching, designing, and implementing a wide
-
area distributed agent
-
based system for

near real
-
time intelligence data access/fusion from heterogeneous data sources.
GNCST is optimized to intelligently process “imperfect cues” from highly diverse (multi
-
INT)
heterogeneous data sources with the application of sophisticated inferencing techn
ologies

in
support of warfighter time critical, in theater situational awareness. Our plan is to apply many of
the proven concepts and “lessons learned” from these tactical intelligence applications to the
military COSR management domain.

Dr. Neria has be
en
a clinician and researcher

in the area
s

of trauma, loss and post
-
traumatic
stress disorder

over the last 15 years. Dr. Neria was awarded the highest Israeli medal of valor
equivalent to the Congressional Medal of Honor
, and subsequently applied his exp
erience in
combat in studies of

various populations
, including

prisoners of war, American and Israeli war
veterans,
and individuals suffering traumatic
loss

and grief.

He
co
-
directs
the Trauma Studies
and Services for New York State Psychiatric Institute
,
a unit created specifically to provide
treatment and to conduct psychosocial and epidemiological research among individuals with
PTSD and Grief reactions.

Dr. Neria has authored numerous publications in the area of PTSD
and is currently leading various res
earch projects that are related to the aftermath of Sep 11,
2001
,

including a nation wide survey on Traumatic Grief in 9/11 victims and a longitudinal study


CTA Proprietary


13

in low income minority, primary care, patients in NYC affected by 9/11 attacks funded by the
Nation
al Institute of Mental Health.

Dr. Koenen

is nationally recognized researcher in the field of trauma related disorders and PTSD
f
rom

a clinical and genetic perspective

in both civilian and military populations
.
In addition to
assuming her position Assista
nt Professor at the Harvard School of Public Health in 2004, she
has served as
Director
, PTSD & Genetics Project Center for Medical & Refugee Trauma,
National Child Trauma Stress Network, Department of Child & Adolescent Psychiatry, Boston
Medical Center,
from 2002 through the present. Prior to joining the faculty at Harvard School of
Public Health, s
he served as Clinical Research Psychologist,
Women’s Health Sciences Division,
National Center for PTSD, Boston VA from 2002
-
2004.

She is the recipient of nume
rous honors
and awards including the 2004 Department of Veterans Affairs, Special Contribution Award, and
the 2005 American Psychopathological Association Robins
-
Guze Award
. She is currently
principle investigator in two ongoing stress related disorder res
earch studies: Developmental
Epidemiology of PTSD and
Genetic Correlates of Acute Stress Response.

Dr. Litz has authored over 100 peer
-
reviewed publications and is the Principal Investigator on
several Department of Veterans Affairs, Department of Defense,

and the National Institute of
Mental Health funded studies
investigating

risk and resilience factors that affect mental health
adaptation to military trauma across the lifespan; various forms of early intervention for trauma
,
including an innovative Inter
net
-
based self
-
management cognitive
-
behavioral therapy
intervention for soldiers returning from OIF/OEF
; and emotional
-
regulation in trauma
-
linked
disorders. Dr. Litz is also currently studying adaptation to traumatic loss as a result of 9
-
11
(along with
Dr. Neria)
and how people cope with the threat of terror in Israel.
Dr. Litz has

recently served on several NIMH/DoD/VA special committees and workgroups to evaluate
screening and intervention strategies in the context of mass violence and to set an agenda

for
primary and secondary prevention of PTSD and related functional impairments from military
trauma.

Dr. Musen has been investigating issues related to knowledge representation and reasoning
methods in biomedical domains for more than two decades. His w
ork has led to the
development of the Protégé system, which is the most widely used domain
-
independent, freely
available, platform
-
independent, open
-
source technology for developing and managing
terminologies, ontologies, and knowledge bases. His research
work has been recognized by the
American Association for Medical Systems and Informatics, which presented Dr. Musen with its
Young Investigator Award for Research in Medical Knowledge Systems in 1989. Dr. Musen
also received an NSF Young Investigator Awar
d in 1992 for his fundamental research in
computer science. Dr. Musen has been elected to the American College of Medical Informatics
and to the American Society for Clinical Investigation.


REFERENCES

1.

National Center for PTSD. The Iraq Clinician Guide, 2
nd

Edition, Washington, DC:
Department of Veterans Affairs; 2004.

2.

Wright KM, Thomas JL, Adler AB, Ness JW, Hoge CW, Castro CA. Psychological
Screening Procedures for Developing U.S. Forces.
Mil Med

(in press).

3.

Hoge CW, Castro CA, Messer SC, McGurk D, Cotti
ng DI, Koffman RL, Combat duty in
Iraq and Afghanistan mental health problems and barriers to care
. N. Engl J Med

2004; 351:
13
-
22.



CTA Proprietary


14

4.

Rona RJ, Hyams KC, Simon W. Screening for psychological illness in military personnel.
JAMA 2005; Vol 293, No 10: 1257
-
1260.

5.

Bliese D, Wright K, Adler A, Thomas J, Hoge CW. Research Report 2004
-
001: Screening
for Traumatic Stress among Redeploying Soldiers. 2004 US Army Medical Research Unit


Europe.

6.


True, W. J., Rice, J., Eisen, S A, Heath, A C, Goldberg, J, Lyons, M

J
, et a
l. (1993). A twin
study of genetic and environmental contributions to liability for posttraumatic stress
symptoms.
Archives of General Psychiatry, 50
, 257
-
264.

7.

Stein, M

B, Jang, K J, Taylor, S, Vernon, P A, & Livesley, W J
.

(2002). Genetic and
environmenta
l influences on trauma exposure and posttraumatic stress disorder: A twin
study.
American Journal of Psychiatry,
159
, 1675
-
1681.8.

8.

McLeod, S., Koenen, K C, Meyer, J
, Lyons, M

J, Eisen, S, True, W, et al.
(2001). Genetic
and environmental influences on the
relationship among combat exposure, posttraumatic
stress disorder symptoms, and alcohol use.
Journal of Traumatic Stress,
14
(4), 259
-
275.

9.

Chantarujikapong, S I, Scherrer, J F, Xian, H, Eisen, S A
, Lyons, M

J, Goldberg, J, et al.
(2001). A twin study of gen
eralized anxiety disorder symptoms, panic disorder symptoms
and post
-
traumatic stress disorder in men.
Psychiatry Research,
103
, 133
-
145.

10.

Koenen, K C, Lyons, M J, Goldberg, J, Simpson, J, Williams, W M, Toomey, R, et al.
(2003). A high risk twin study of c
ombat
-
related PTSD comorbidity.
Twin Research,
6
, 218
-
226.

11.

Segman, R H, Shefi, N, Goltser
-
Dubner, T, Friedman, N, Kaminski, N, & Shalev, A. Y.
(2005). Peripheral blood mononuclear cell gene expression profiles identify emergent post
-
traumatic stress disord
er among trauma survivors.
Mol
ecular

Psychiatry
.

12.

Olsson CA, Anney RJ, Lotfi
-
Miri M, Byrnes GB, Williamson R, Patton GC. Association
between the COMT Val 158Met polymorphism and and propensity to anxiety in an
Australian population
-
based longitudinal study
of adolescent health.
Genetic Psychiatry

2005
June; 15(2): 109
-
115.


13.

Small, K M, Mialet
-
Perez, J., Seman, CA, Theiss, C T, Brown, K M, & Liggett, S B. (2004).
Polymorphisms of cardiac presynaptic alpha2C adrenergic receptors: Diverse intragenic
variability

with haplotype
-
specific functional effects.
Proceedings of the National Academy
of Sciences of the United States of America,
101
(35), 13020
-
13025.

14.

Tsuda, K., Goldstein, M, & Masuyama, Y (1990). Neuropeptide Y and galanin enhance the
inhibitory effects of
clonidine on norepinephrine release from medulla oblongata of rats.
American Journal of Hypertension,
3
(10), 800
-
802.

15.

Lappalainen, J., Zhang, L., Dean, M., Oz, M., Ozaki, N., Yu, D. H., et al. (1995).
Identification, expression, and pharmacology of a Cys23
-
Ser23 substitution in the human 5
-
HT2c receptor gene (HTR2C).
Genomics,
27
(2), 274
-
279.

16.

Hariri, A. R., Mattay, V

S, Tessitore, A., Kolachana, B, Fera, F, Goldman, D., et al. (2002).
Serotonin transporter genetic variation and the response of the human amy
gdala.
Science.,
297
(5580), 400
-
403.

17.

Caspi, A, Sugden, K, Moffitt, T E, Taylor, A, Craig, I W, Harrington, H, et al. (2003).
Influence of life stress on depression: moderation by a polymorphism in the 5
-
HTT gene.
Science,
301
(5631), 386
-
389.



CTA Proprietary


15

18.

Chen, Z. Y, Pa
tel, P D, Sant, G, Meng, C X, Teng, K K, Hempstead, B L, et al.
(2004).
Variant brain
-
derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking
and activity
-
dependent secretion of wild
-
type BDNF in neurosecretory cells and cortical
ne
urons.
Journal of Neuroscience,
24
(18), 4401
-
4411.

19.

Egan, M. F., Kojima, M, Callicott, J H, Goldberg, T E, Kolachana, B S, Bertolino, A, et al.
(2003). The BDNF val66met polymorphism affects activity
-
dependent secretion of BDNF
and

human memory and hippocam
pal function.
Cell,
112(2), 257
-
269.

20.

Pezawas, L, Verchinski, B A, Mattay, V S, Callicott, J H, Kolachana, B S, Straub, R E, et al.
(2004). The brain
-
derived neurotrophic factor val66met polymorphism and variation in

human cortical morphology.
Journal of Ne
uroscience,
24(45), 10099
-
10102.

21.

Strauss, J, Barr, C
L
, George, C J, King, N, Shaikh, S, Devlin, B, et al. (2004). Association
study of brain
-
derived neurotrophic factor in adults with a history of childhood onset mood
disorder.
American Journal of Medical

Genetics,
131 B
(1), 16
-
19.

22.

Tsai, S

J
, Cheng, C Y, Yu, Y W, Chen, T J, & Hong, C J (2003). Association study of a
brain
-
derived neurotrophic
-
factor genetic polymorphism and major depressive disorders,
symptomatology, and antidepressant response.
American J
ournal of Medical Genetics. B
Neuropsychiatric Genetics,
123
(1), 19
-
22.

23.

Binder, E B, Salyakina, D, Lichtner, P, Wochnik, G M, Ising, M, Putz, B, et al. (2004).
Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes
and rapid

response to antidepressant treatment.
Nat Genet,
36(12), 1319
-
1325.

24.

Yehuda, R. Posttraumatic stress disorder,
N. Engl J Med

2002 346(2):108
-
114.

25.

Neylan TC, Brunet A, Pole N, Best SR, Metzler TJ, Yahuda R, Marmer CR. PTSD
symptoms predict waking salivary c
ortisol levels in police officers.
Psychoneuroendocrinology

(2005)

30:373
-
381.

26.

Morgan CA, et al. Hormone Profiles in humans experiencing military survival training.
Biol

Psychiatry

2000
; 47:891
-
901.

27.

Wong ML, et al. Pronounced sustained central hyperadrene
rgic function in major depression
with melancholic features: relation to hypercortisolism and cortiotropin
-
releasing hormone.
Proc Natl Acad Sci USA

2000
; 97
-
325
-
330.

28.

Shalev AY, Sahar T, Freedman S. Prospective study of heart rate response following trauma

and the subsequent development of posttraumatic stress disorder.
Arch Gen Psychiatry

1998
;
55:553
-
559.

29.

Geracioti TD, et al. CSF norepinephrine concentration in posttraumatic stress disorder.
Am J

Psychiatry

(
2001)

158: 227
-
1230.

30.

Brewin CR, Andrews E, Vale
ntine JD. Meta. Meta
analysis

of risk factors for posttraumatic
stress disorder in trauma exposed adults.
J of Consulting and Clinical Psychology

2000
, Vol
68, No 5: 748
-
766.

31.

Neylan OC, et al. association between childhood trauma and catecholamine respons
e to
psychological stress in in police academy recruits.
Biol Psychiatry

2005

Jan 1; 57(21): 27
-
32.

32.

Rasmusen AM, et al. low baseline and yohimbine
-
stimulated plasma neuropeptide Y levels
in combat
-
related PTSD.
Biol Psychiatry

2000; 47:526
-
539



CTA Proprietary


16

33.

Bryant RA, H
arvey AG. Acute Stress Disorder: A handbook of Theory, Assessment, and
Treatment. Washington , DC 2000, American Psychological Association.

34.

Beck AT, Ward CH, Mendelson, et al. An inventory for measuring depression.
Arch Gen
Psychiatry

1961
;4:561
-
571.

35.

Spiel
berger CD, Gorsuch RL,Lushene RE: Manual for the State
-
Trait Anxiety Inventory
(Self
-
Evaluation Questionnaire). Palo Alto, CA:
Consulting Psychologist Press
, 1970.

36.

Connor KM, Davidson JR: Development of a new resilience scale: the Connor
-
Davidson
R
esilienc
e
S
cale (CD
-
RISC).
Depress Anxiety 2003
; 18(2): 76
-
82.

37.

Boury
-
Brisset, A.,
Ontology Based Approach for Information Fusion
, ISIF, 2003.

38.

Hudson, L., Ware, B., Laskey, K., Mahoney, S., An Application of Bayesian Networks to
Antiterrorism Risk Management for M
ilitary Planners
, 2001, GMU Technical Report

available at

http://ite.gmu.edu/~klasky/papers/Antiterrorism.pdf

39.

Aisen, C.,
Computer Assisted Standing Orders Improve Adult Immunization Rates
, Medical
News Today, 2004

40.

Buckeridge DL, Graham J, O’Connor MJ, Cho
y MK, Tu SW, Musen MA. Knowledge
-
Based
Bioterrorism Surveillance. Proceedings of the American Medical Informatics Association
Symposium 2002:76
-
80.

41.

Beinlich, Ingo, H. J. Suermondt, R. M. Chavez, and G. F. Cooper (1989) "The ALARM
monitoring system: A case
study with two probabilistic inference techniques for belief
networks" in Proc. of the Second European Conf. on Artificial Intelligence in Medicine
(London, Aug.), 38, 247
-
256. Also Tech. Report KSL
-
88
-
84, Knowledge Systems
Laboratory, Medical Computer Sci
ence, Stanford Univ., CA.

42.

Pearl, Judea (1988) Probabilistic Reasoning in Intelligent Systems: Networks of Plausible
Inference, Morgan Kaufmann, San Mateo, CA. 2nd edition 1991.


43.

Gauri Mahajani, Y. Alp Aslandogan (2003) Evidence Combination in

Medical Data
Mining
,
Technical Report CSE
-
2003
-
23
,
Department of Computer Science and Engineering
,
University of Texas at Arlington