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Relationships matter: contextualizing developmental outcomes of high risk infants

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Relationships matter: contextualizing developmental outcomes of high risk infants

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Content 1

Master’s of Clinical and Biomedical Investigations Thesis
UNIVERSITY OF SOUTHERN CALIFORNIA

May, 2015

Title:
Relationships Matter: Contextualizing Developmental Outcomes of High Risk Infants

Author:
Douglas Vanderbilt

Master’s Committee Members:
Stanley Azen
Istvan Seri
Cecilia M. Patino

2

Table of Contents
Sections Page

1. Cover Letter 3
2. Project Narrative 4
3. Abstract 5
4. Specific Aims 6
5. Research Strategy 7
6. Targeted Planned Enrollment 15
7. References 16

Supplementary information

8. Candidate Background 19
9. Career Development Goals 20
10. Career Development Activities 21
11. Training in Responsible Conduct of Research 24
12. Protection of Human Subjects 25
13. Inclusion of Women and Minorities 28
14. Inclusion of Children 29
15. Institutional Environment 30
16. Facilities and Resources 31

3

Cover Letter

Master’s Thesis Committee:

The original plan for my Master’s Thesis was the production of a NIH Mentored Patient-Oriented Research
Career Development Award (K23), entitled Relationships Matter: Contextualizing Developmental Outcomes of
High Risk Infants. This application was assigned to and reviewed by the Biobehavioral and Behavioral
Sciences Subcommittee of the Child Health and Human Development study section (CHHD) of the Eunice
Kennedy Shriver National Institute of Child Health and Human Development (NICHD). I received the
summary sheets on August 27, 2014 with an impact score of 42.

Since that time, I attempted to assess the changes that were necessary to be competitive for a resubmission.
The bulk of the focus has been on identifying content and process mentors to improve both my research and
training plans. I believe now I am in contact with individual researchers who understand the conceptual
framework and methods and can advise me on improvements needed. These new relationships will lead to a
resubmission for July, 2015.

Given the scope of these changes and the process and time needed to achieve them, I am requesting that the
current submitted grant proposal be my master’s thesis. This will be a statement of a work in progress. The
time commitment of the resubmission extends beyond the current semester graduation constraints.

Thank you for the mentorship and suggestions leading to this successful master’s thesis submission.

Sincerely,

Douglas Vanderbilt
Master’s of Clinical and Biomedical Investigation Candidate 2015

4

Project Narrative

Neonatal Intensive Care Unit (NICU) experiences are costly, associated with poor infant development, and
highly stressful to the caregiver and the infant-caregiver relationship – yet no comprehensive process model
exists to describe the interplay of medical and environmental factors that determine development following a
stay in the NICU. Support from this K23 mentored career development award will support the candidate to
develop expertise in the multiple disciplines united by his research, with the ultimate goal of developing a
theoretically informed preventive intervention to improve long-term outcomes of vulnerable NICU survivors.

5

Abstract
More than 10% of all US-born infants require an admission to a neonatal intensive care unit (NICU); in
addition to high costs, these infants are likely to have poorer neurodevelopmental outcomes than healthy term
infants. NICU experiences are highly stressful to the caregiver and the infant-caregiver relationship, which may
harm infant neurodevelopment beyond the effect of medical severity. Yet, no comprehensive process model
that includes medical, caregiver, and relationship factors guides targeted preventive interventions. To improve
the long-term outcome of high-risk infants (HRI), we need a deeper understanding of the interplay of the
medical and psychological factors that determine development following a stay in the NICU.
The long-term goal of the proposed study is to examine the impact of caregiver NICU generated traumatic
stress symptoms on developmental outcomes of HRI. This prospective cohort study tests an innovative
conceptual model in a population with a broad range of medical severity to assess mediators of
neurodevelopmental outcomes at 6 and 12 months. The specific aims of this proposal are to: 1) Describe
delayed effects of caregiver traumatic stress from the NICU on the neurodevelopmental outcomes of HRI; 2)
Assess the concurrent effects of caregiver traumatic stress symptoms from the NICU on the
neurodevelopmental outcomes of HRI; and 3) Evaluate whether caregiver traumatic stress and caregiver-
infant interaction dysynchrony explain the persistent effects of medical severity on HRI neurodevelopmental
outcomes. To successfully integrate the psychological perspective into this biomedical context, the career
development plan accompanying this research project creates a foundation for designing and testing
theoretically informed preventive interventions.
As a developmental-behavioral pediatrician focused on HRI both clinically and in research, I am well
positioned to bridge the medical and psychological literatures to develop a comprehensive process model to
inform future preventive approaches. This career award will support my development into an independently
funded national leader in the area of HRI developmental consequences. To acquire these clinical research
skills, my career development plan refines my expertise in four key areas: 1) Application of developmental
systems and infant mental health theories to HRI neurodevelopment; 2) Development of a theoretical
understanding of the role of biomedical and psychological factors in HRI neurodevelopment; 3) Relationship
assessment and modeling methodologies; and 4) Longitudinal cohort designs, multivariable methods
appropriate for longitudinal data and management of multidisciplinary research teams, My career development
plan is well supported by the University of Southern California, an ideal environment given their access to
unique patient populations, interdisciplinary mentors, interdepartmental collaborations, and track record of
exceptional mentorship of physician-scientists in developmental assessment.

6

Specific Aims
In the United States, almost 400,000 infants are treated annually in the Neonatal Intensive Care Unit (NICU),
where they undergo intensive medical interventions for premature birth complications or other life-threatening
medical illnesses. These high-risk infants (HRI) are at lifelong risk for numerous medical, behavioral, and
neurodevelopmental problems,
1
while their caregivers have been shown to suffer psychological distress (taking
the form of depressive or traumatic stress symptoms) as a result of their participation in the NICU
experience.
2,3
Thus far, studies of these HRI outcomes typically model medical risk factors entirely separately
from psychological risk factors such as caregiver traumatic stress and infant-caregiver relationships. Yet these
are critical risk factors for adverse neurodevelopment and behavior outcomes.
3,4,5,6
Integrating new
knowledge about medical and psychological risk factors is critical to preventing the negative
developmental outcomes of HRI. Yet there remain insufficient interactions between medical and
psychological risk factors, resulting in a paucity of effective interdisciplinary approaches to improve HRI
outcomes.
7

My long-term goal is to examine the impact of caregiver traumatic stress symptoms from the NICU in order to
improve HRI outcomes. The overall objective of this application is to model the effects of caregiver
posttraumatic stress symptoms and quality of the infant-caregiver relationship, beyond the effects of medical
severity, on the neurodevelopmental outcomes of HRI. The career development plan focuses on investigating
a comprehensive process model that simultaneously includes medical, caregiver, and relationship factors to
determine and improve the outcomes of these HRI populations. The main hypothesis motivating this research,
based on the Developmental Systems Approach Model,
7
is that caregiver traumatic stress symptoms from the
NICU will negatively impact the infant-caregiver relationship and result in poorer neurodevelopmental
outcomes. This research approach is novel because it focuses on 1) a medically and environmentally driven
conceptual model, 2) an infant cohort comprising a wide range of gestational age and medical severity, and 3)
the application of a comprehensive process model to modifiable neurodevelopmental outcomes.
In this prospective cohort study, I will recruit a sample of premature and term HRI who have required both
NICU admission and an intensive intervention such as head cooling and extracorporeal membrane
oxygenation for medical conditions such as hypoxic-ischemic encephalopathy and respiratory distress
syndrome. I will assess: 1) infant medical severity with a composite physiological scale
8
and neuroimaging; 2)
caregiver psychological distress with validated traumatic stress
9
and depressive symptom questionnaires
10
; 3)
infant-caregiver relationship with an observation-based assessment
11
; and 4) developmental outcomes through
a widely validated and normed administered scale.
12
These variables will be assessed in infants and
caregivers longitudinally at 2, 6, and 12 months, corrected for gestational age in established HRI clinic visits.
Multilevel modeling for repeated measures will test these hypotheses. The specific aims are as follows:

Aim 1: Investigate the delayed effects of caregiver traumatic stress from the NICU on the neurodevelopmental
outcomes of HRI.
Hypothesis 1: Controlling for medical severity, greater caregiver traumatic stress at 2 and 6 months will be
associated with worse HRI neurodevelopmental scores at 6 and 12 months in 125 infant-caregiver pairs.
Aim 2: Assess the concurrent effects of caregiver traumatic stress symptoms from the NICU on the
neurodevelopmental outcomes of HRI.
Hypothesis 2: Controlling for medical severity and prior caregiver traumatic stress, greater caregiver
traumatic stress at 6 and 12 months will be associated with worse HRI neurodevelopmental scores at 12
months in 125 infant-caregiver pairs.
Aim 3: Evaluate whether caregiver traumatic stress and its effects on the caregiving environment at least
partially explain the persistent effects of medical severity on HRI neurodevelopmental outcomes.
Hypothesis 3A: Caregiver traumatic stress mediates the relationship between medical severity and infant
neurodevelopmental outcomes.
Hypothesis 3B: Quality of the infant-caregiver interaction will fully mediate the relationship between
caregiver traumatic stress and infant neurodevelopmental outcomes.

As my focus shifts from clinical and training roles toward an independent research career, this K23 will support
my interactions with well-established mentors in multiple disciplines united by my research, creating the
foundation for R01 funding to develop evidence-based preventive interventions. This study has the potential to
prevent poor outcomes among highly vulnerable infants by understanding the interplay between biological and
psychological risk factors.

7

Research Strategy
A. SIGNIFICANCE
A1. High Cost of NICU Graduation. More than 10% of all US-born infants – over 400,000 per year – will
require an admission to a neonatal intensive care unit (NICU) or special care nursery
13
, generating an average
hospital charge of $76,000 per infant
6
. While half of these NICU admissions are due to the medical problems
associated with prematurity, another large share are from term infants with medical complications.
6
The
Institute of Medicine estimates that the prematurity cohort alone consumes over $26 billion in economic
output.
7
Well over half of those costs are from lifesaving medical interventions, but another 28% of the costs
are related to longer-term neurodevelopmental sequelae.
7
The immediate costs, as well as the initial
neurodevelopmental trajectories of these medically severe high-risk infants (HRI), are largely determined by
the lifesaving intensive interventions delivered in the NICU. Caregivers and society at large bear the brunt of
the costs through lost economic productivity and infant developmental, child educational, and rehabilitative
therapy services. Little is known about how to mitigate the costs and target the drivers of HRI outcomes after a
NICU experience.
A2. NICU Neurodevelopmental Outcomes: Medical Risk. Twenty-first-century enhanced technological care
includes whole body cooling to reduce reperfusion injury, high frequency oscillating ventilation for respiratory
collapse, and extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure refractory to
conventional medical management, but these lifesaving interventions have been linked to neurodevelopmental
impairments in studies of populations with and without cardiac disease.
8
The rates of neurodevelopmental
impairment in ECMO recipients without cardiac disease range from 8% to 72% depending on the assessment
technique and age of the study population; intellectual disability, cerebral palsy, behavioral problems, learning
disabilities, and various developmental delays are common sequelae.
9-12
Additionally, later-onset hearing loss
has been found and contributes to these neurodevelopmental morbidities. While most risk models use medical
severity history as the predictor of outcomes, emerging evidence in an ECMO patient cohort suggests that
abnormal postnatal neuroimaging may predict those at higher risk of later developmental problems,
14,15
as was
previously found for other perinatal causes of brain injury in the NICU.
16-24
Although not all HRI have
identifiable brain injury on clinical neuroimaging, up to 50% do have abnormal findings putting them at risk of
later neurodevelopmental problems.
14,17,25-27,32

A3. The NICU “Intensive Care”: An Emotional Toll to Caregivers. Often overlooked in the imperative of
infant survival are the effects of the NICU experience on the family caregivers. Though necessary, lifesaving
technologies such as ECMO in the NICU are highly invasive and can be frightening to family caregivers. The
increasing use of ECMO has contributed to the increase in survival of neonates without cardiac disease from
50% in the 1990s to an almost 90% survival in the first decade of the 21st century.
11,28,29
Nevertheless, the
experience of having an infant receiving these invasive interventions in the NICU creates emotional
consequences for the primary caregivers who exhibit elevated rates of depression and anxiety symptoms when
their infant is born preterm or had a stay in the NICU.
3
We recently showed that the NICU experience is a
specific traumatic stressor event that generates traumatic stress symptoms in caregivers.
30,31
Very few studies
have followed the course of symptoms experienced by caregivers or assessed their consequences to the
developing HRI.
2,32

A4. Caregiving Environment: Echoes of NICU Traumatic Stress. The degree of caregiver-infant
relationship attunement is a critical mechanism for later infant outcomes.
33
It is theorized that infants learn
through a stable primary relationship with a caregiver.
34
This critical early learning environment can be
disrupted if the caregiver suffers from depression or traumatic stress, eventually resulting in reduced infant
potential.
35
The NIH has acknowledged the importance of the role of caregiver mental health for HRI
populations through the funding of interventions for caregiver traumatic stress and depressive symptoms for
infants born premature. Despite this acknowledgement, research on the consequences of caregiver
posttraumatic stress symptoms on HRI outcomes has been limited. Traumatic stress symptoms in caregivers
are important predictors of children’s sleep and eating problems
32,36
, and cognitive performance.
37
Caregiver
depression, also quite prevalent, often co-occurs with posttraumatic stress symptoms and affects infant
physical, developmental, and behavioral health outcomes.
38, 41
Caregivers’ stressful experiences from the
NICU of their preterm infants diminish the quality of the infant-caregiver relationship, and the resulting
maladaptive interactions lead to more behavioral symptoms and lower developmental scores for the infant.
3

Prematurity itself has been linked to less adaptive parenting styles such as less sensitive and more controlling
and protective caregiver behaviors,
36,39
which may increase the risk of infant social/emotional, communication,
and behavioral problems.
5
These infants often have ongoing medical problems that serve as traumatic
8

reminders and ongoing stressors.
40
Despite these few studies, the sequelae of caregiver traumatic stress on
HRI neurodevelopment is often not considered for a range of gestational ages or medical severity and rarely in
intervention studies.
42,43,44

A5. Key Contextual Factors Driving Outcomes are Often Unmeasured. Many studies in HRI adopt either a
medical or environmental conceptual framework in approaching neurodevelopmental outcomes. Caregiver
age, ethnicity, and education level are used prominently in studies of long-term educational outcomes, but
have been considered as confounders in studies of medical risks to HRI outcomes.
3,45
This narrow
investigative approach creates an incomplete picture as to the origins of the outcomes of interest, and could
obscure the important targets of post-NICU intervention. To accurately understand the infant medical severity
consequences the key caregiver factors driving the developmental outcome must be assessed and modeled
simultaneously and longitudinally with the medical risk. The conceptual model for the proposed research
(Figure 1), patterned after the Developmental Systems Approach,
4
addresses this deficiency:

Figure 1:

This explanatory framework identifies two potential pathways between HRI medical vulnerability and future
outcomes, one via medical severity and the other via the caregiver psychological health and patterns of
interaction with the infant. The model incorporates three components represented by: (1) the “Infant Medical
Severity,” based on perinatal risks of illness and treatment; (2) the “Social Environment,” which includes other
contextual factors such as socioeconomic status and ethnicity that factor into the caregiving environment; and
(3) the “Caregiver Psychological Distress,” with traumatic stress and depressive symptoms as indicators. The
degree of attunement in the interaction will be assessed between infant and caregiver as the “Infant-Caregiver
Relationship.” Finally, “Developmental Outcomes,” including infant neurodevelopment and cognitive, language,
motor, socio-emotional and adaptive functioning, are joint products of medical severity and relationship factors.
A6. Identification of Targets to Improve Outcomes. A comprehensive approach including traumatic stress
symptom screening is needed to better understand and describe the outcomes of our intensive care
treatments.
3
The data generated on caregiver distress and infant development will directly inform how family-
centered care is delivered in the NICU and lead to later clinical trials. This study will also determine the relative
impact of psychosocial risk factors that can inform future post-hospital preventive interventions for caregivers
and HRI. For example, more comprehensive mental health screening, support groups, caregiver psychological
distress treatment, or infant enrichment may all be needed. This caregiver mental health focus area has
reached national importance as seen from communiqués from the March of Dimes and other perinatal
organizations recommending routine depression screening.
47
The proposed study will inform current family-
centered interventions in the NICU and will help to design post-NICU preventive approaches.
4,46
This
comprehensive research has the potential of improving the lives of stressed caregivers, and thus enhancing
the developmental outcomes and lowering the therapeutic costs of these high-cost medical survivors.
B. INNOVATION
The main goal of the proposed study is to define a direct relationship between caregiver mental health and
infant neurodevelopment. This proposal features several key innovations:
B1. A Novel Context Conceptual Model. No published research in the US has yet assessed the
consequences of NICU-based caregiver traumatic experiences on the infant’s later neurodevelopmental
functioning above and beyond established medical severity risk factors. The proposed research uses a
comprehensive conceptual model (Figure 1), which integrates medical, caregiver, and relationship factors. The
use of a developmental outcome model is highly innovative to the medical setting. This explanatory framework
simultaneously models medical and environmental determinants of neurodevelopmental outcomes, which is a
major advantage. This novel perspective will allow us to understand the relative importance of medical,
Infant
Medical
Severity
Caregiver Psych
Distress
Infant-
Caregiver
Relationship
Developmental
Outcomes
Social
Environment
9

caregiver, and relationship factors on infant outcomes, a necessary first step to identify more effective and
potentially modifiable treatment strategies that will improve infant outcomes.
B2. Expanded Perspectives to Improve NICU Research. NICU-based research has not simultaneously
studied preterm and term infants, despite the latter being also at risk. This study proposes that a common set
of medical severity risks produces caregiver traumatic stress reactions that lead to impaired relationship
interactions and poor infant neurodevelopment. This study will examine these risk variables in a combined
cohort of premature and term infants. Incorporating the less-studied term populations will enhance our ability to
understand the range of potential outcomes that are shaped by caregiver experiences in the NICU. This will
strengthen the application of our findings to all medically intensive HRI receiving life-saving interventions.
B3. Linking Caregiver Distress to Infant Outcomes. Current studies do not acknowledge that infant
developmental outcomes are impacted by HRI-caregiver distress. Instead, medical severity factors are the
main independent variables predicting primarily neurologic or medical outcomes; or, alternatively, caregiver
psychological variables are seen as the primary driver of behavioral or socio-emotional outcomes. This study
addresses that deficiency with the testing of an innovative model that has a primary outcome focus on a wide
range of the infant neurodevelopmental outcomes but includes both independent pathways.
C. APPROACH
C1.1. Overview. This is a longitudinal neurodevelopmental cohort study involving term and preterm infants.
This prospective cohort study will incorporate medical severity risk data from the infants’ electronic medical
records with clinician assessment of infant neurodevelopment and infant-caregiver relationship and self-
reported caregiver psychological distress. Medical, psychological, developmental, and social variables will be
simultaneously tested in multiple linear regression models to compare the relative impact of each distinct
variable type on neurodevelopmental outcomes. The project will be completed over a 3-year enrollment and
follow-up period (see Table 1 Timeline below).
C1.2. Patient Population. Patients will be recruited from the CHLA High-Risk Infant Follow-up (HRIF) clinic
which has a high acuity patient mix. . These HRI represent a range of gestational ages. These patients who
have survived with an intensive intervention (extracorporeal membrane oxygenation, circulatory support, total
body cooling, or ventilator support) will be enrolled with their primary caregivers in this longitudinal study to
understand contextual and biologic risk factors for neurodevelopmental outcomes. Because the purpose of the
study is to understand two distinct pathways to neurodevelopment, the recruitment process was designed to
support enrollment of a heterogeneous NICU sample. Due to the severity of the underlying medical conditions
necessitating intensive interventions, if these infants were to not receive the intervention, the probable outcome
would be death. This makes a similar-severity, non-intensive intervention comparison group not feasible or
ethical for entering into the study design. However, based on the intensity of both the medical severity and
potential traumatic reactions, we expect to see a full range of traumatic stress and neurodevelopmental
outcomes.
C1.3. Selection Criteria.
Inclusion: This study’s inclusion criteria will specifically target HRIs who have had an intensive medical
interventions, which include those receiving extracorporeal membrane oxygenation, circulatory support, total
body cooling, or ventilator support. Infants must be eligible for the CHLA HRIF clinic (i.e., all infants born less
than 32 weeks and/or 1500 grams or having a potential neurodevelopmental risk-intensive intervention)
48
;

have
experienced an intensive medical intervention (described above); and have English- or Spanish-speaking
caregivers such that validated neurodevelopmental outcome assessment tools may be used. Presenting
primary caregivers must be the legal guardian of the infant being enrolled.
Exclusion: Subjects will be excluded if they are unable to enroll in the HRIF clinic or if they received
interventions for congenital heart disease as their brain development in utero may be affected by the
underlying heart disease; this group of patients is qualitatively different from other NICU survivors and is
expected to have a different long-term neurodevelopmental outcome compared to neonates receiving
interventions for non-cardiac pathologies. Exclusion criteria also include major infant congenital or brain
abnormality, defined genetic syndrome, and caregivers unable to complete the follow-up visit or measures due
to cognitive limitations or language.
C1.4. Selection, Recruitment, and Tracking. On a weekly basis, the Principal Investigator (PI) will identify
eligible potential participants from those referred to the HRIF clinic for the initial 2-month corrected visit using
patient information in the electronic medical record or discharge summary. Patients to our clinic are primarily
referred from NICU located at CHLA, Hollywood Presbyterian Medical Center, Good Samaritan Hospital, and
10

Los Angeles County+USC Medical Center, though a small percentage may be referred by other outlying NICU.
In fiscal year 2012, over 80 infants were seen in the HRIF clinic at the 6- and 12-month visits.
After eligibility determination by the PI, the research assistant (RA) will discuss the disposition of eligible
participants with the NICU attending, fellow, resident, NICU nurse or HRIF coordinator prior to contacting the
family. The RA will approach the caregiver near the time of discharge from the NICU or upon referral to the
HRIF clinic, either in person or by phone, to explain the study and obtain consent. A recruitment and tracking
database will be developed and maintained to establish consent and follow-up rates and ensure recruitment
sample size targets are met. Study visits will occur at 2, 6, and 12 months corrected age, and the RA will
coordinate all research visits with the HRIF nurse coordinator. The RA will contact the caregiver prior to each
research visit to preview what the participants should expect regarding time and activities. If a caregiver needs
a Spanish interpreter, the RA will use the phone translation service that can be accessed the day of the
appointment. Prior to each visit, the RA will prepare the necessary materials, including HIPAA and consent
documents as needed, a networked computer, paper measures, and incentives.
C1.5. Measures/Instruments. The primary Infant Medical Severity covariate variable is the perinatal risk
factors and brain injury. Perinatal risk factors will be measured using a composite measure of medical illness
that assesses risk of neonatal mortality. We will use SNAPPE-II, which incorporates gestational age, sex, birth
weight, temperature, base excess, illness severity and other physiologic respiratory, renal, and neurologic
parameters.
50,51
Descriptive patient-related factors, such as gestational age at delivery, birth weight and length
of stay will be recorded. Additional descriptive procedure-related variables will be documented to characterize
the NICU interventions, such as diagnostic insult, ECMO type and time, ventilator type and duration, and
cooling type. Brain Injury evidence will be obtained using clinically obtained neuroimaging through head
ultrasound or MRI. The use of neuroimaging in the NICU is routine for prematurity (<29 weeks) and a clinical
indication for any infant with critical illness or surgery greater than 29 weeks gestation. Patients fitting this
study’s inclusion criteria are all eligible for neuroimaging at term equivalent and greater than 80% of the HRIF
patients receive this imaging. Any lesion seen on neuroimaging that is associated with neurodevelopmental
impairment will be coded as a positive finding. Those will include intraventricular hemorrhage grade III-IV,
cystic periventricular leukomalacia, ventriculomegaly and/or hydrocephalus, microcephaly, infarctions,
porencephalic/Dandy-Walker cysts, or bilateral other cysts.
52
In a sub-analysis for the patient subset who has
undergone MRI, we will use the scoring system developed by Kidokoro, which codes total cortical GM
abnormalities, deep GM volume, and cerebellar volume scores into 4 grades: no (total score, 0), mild (total
score, 1), moderate (total score, 2), and severe (total score >3).
53
The MRI and ultrasound scans will be coded
by a neuroradiology researcher.
The primary Developmental Outcome variable is the infant neurodevelopmental score, which will be
measured by the Bayley Scales cognitive, language, motor, social–emotional, and adaptive domains at 6 and
12, months which is a routine assessment in the HRIF clinic.
54
The Bayley Scales are considered to be the
gold standard of developmental assessment from birth to 42 months; they have been used in numerous HRI
outcome studies
55
and correlate highly with the Wechsler Preschool and Primary Scale of Intelligence–Third
Edition (r = .83).
54
The neurodevelopmental assessments will be overseen by the neuropsychologist from the
CTSI Clinical Trials Unit, who has participated in numerous methodologically rigorous neurodevelopmental
outcome studies using this instrument. The Amiel-Tison examination will be used to assess neurological status
of active tone, passive tone, and fine and gross motor function.
56
This examination is part of the HRIF clinic
visit and will be performed by the PI, a trained developmental-behavioral pediatrician.
Caregiver environment variables include Caregiver Psychological Distress and Infant-Caregiver
Relationship. While we expect that key predictors of psychological distress will be depressive and traumatic
symptomatology, we will be open to alternate measures that may be a better model fit. Depressive symptoms
will be measured by the Center for Epidemiologic Studies Depression Scale Revised (CESD-R)
57
and
traumatic stress by the Perinatal Post-traumatic Stress Disorder Questionnaire (PPQ)
58
. The CESD-R is a 20-
item self-reported measure that assesses symptoms of depression in community and postpartum samples.
Respondents indicate how many days during the last week they experienced several depressive symptoms.
The PPQ is a 14 item self-report validated questionnaire based on DSM criteria that assesses the range of
traumatic stress symptoms over a one month time period using a Likert scale.
58
The PPQ was designed to be
administered to parents after the birth of their child to determine possible traumatic stress symptoms related to
that birth. A positive screen is suggestive of a probable posttraumatic stress disorder diagnosis when a
respondent acknowledges 6 or more symptoms.
11

Although we believe that the CES-D and PPQ measures will capture the essential variance in caregiver
distress domain, it is possible that different aspects of the NICU environment may ultimately show stronger
associations with the proposed outcomes. To fully understand the caregiver’s psychological experience, we will
include three alternate measures, which will include The Davidson Trauma Scales (DTS), a 17-item scale
assessing symptoms of posttraumatic stress disorder; the Traumatic Events Questionnaire (TEQ),
61
an
interview comprised of 11 questions on 9 potential traumatic events that a caregiver may have experienced;
and the Parental Stressor Scale: Neonatal Care Unit (PSS:NICU),
62
a 34-item scale evaluating parents’
perceptions of the stressors due to the infants’ NICU stay. We are not initially planning to use the DTS, TEQ, or
PSS:NICU for more than descriptive purposes as they will likely have a high degree of collinearity with our
primary measures; however, collecting them will allow us to fully describe all aspects of NICU-related traumatic
stress in the caregivers, and they may function as replacement measures in the event of multicollinearity
between the CES-D and PPQ (see section C2.2, analysis of Specific Aim 2).
The infant-caregiver relationship interaction will be measured at 6 and 12 months corrected gestational age by
The Nursing Child Assessment Satellite Training (NCAST) Parent-Child Interaction Feeding and Teaching
scales. The NCAST is a clinician-administered tool that includes observations on 73 items organized around
six constructs of parent-child interaction, including Sensitivity to Cues; Response to Child's Distress; Social-
Emotional Growth Fostering; Cognitive Growth Fostering; Clarity of Cues; and Responsiveness to Caregiver,
with higher scores indicating higher quality interactions. The NCAST is predictive of later relationships and
behavior, including IQ.
63
The scale has been normed on a large sample of children from birth to 36 months of
age and shown to have sufficient breadth to allow for cultural differences, including among Hispanic/Latino and
African-American samples.
64,65,66
The NCAST assessment will be performed and scored by a research-trained
infant mental health clinician, who will be masked to caregiver distress and neurodevelopmental outcomes.
Additionally, other Background socio-demographic variables will be measured at the 2-month visit, including
race/ethnicity, socio-economic status, insurance status, caregiver age at delivery, caregiver level of education,
multiple gestation, number of children in home, developmental services (type of therapy, duration), and
previous experience of infant in NICU. See Figure 2.
Figure 2:

C1.6. Data Collection and Management. A REDCap (Research Electronic Data Capture) database will be
developed and utilized for this study. REDCap is a secure, web-based application for data capture that
provides an intuitive interface for validated data entry, automated export procedures for seamless data
downloads to common statistical packages, and procedures for importing data from external sources. Once a
caregiver has consented to participate, the RA will abstract the infant’s medical record to obtain the medical
severity variables and enter them into the REDCap database. Questionnaires will be administered via REDCap
in Spanish and English at the 6
th
grade reading level. For low literacy caregivers, the RA will be available to
assist. The relationship and neurodevelopmental assessment results will be entered into the database after
scoring by the clinician. The database will be stored on a password-protected server with limited research
personnel access. Preliminary univariate reports will be run on a bimonthly basis to check for errors and
guarantee quality. The PI will review the patient folders and database, including notes about unusual events,
and will assign a data quality code to the patient’s data within the research database.
The clinical and survey assessments will occur in the HRIF clinic. Infants will be assessed at 2, 6 and 12
months corrected age, which are the standard visits in the clinic, and caregivers will be seen concurrently. The
RA will use the networked computer to obtain questionnaires from the caregiver at all visits. As the caregiver
measures include assessments of suicidality or extreme distress, a standard procedure previously developed
Birth
• Trauma event
• Biological injury
• Demographics
6 months
• Caregiver symptoms
• Infant-caregiver
relationship synchrony
• Neurodevelopmental
outcomes
• Social risks
12 months
• Caregiver symptoms
• Infant-caregiver
relationship synchrony
• Neurodevelopmental
outcomes
• Social risks
12

for the KL2 pilot study, including a mental health consultation by a licensed clinical social worker and/or on-call
child psychiatrist, will be used to manage the mental health risk of caregivers endorsing suicidal or highly
distressed thoughts. In addition to facilitating the self-report survey, the RA will instruct or assist the caregiver
in completing the Bayley Adaptive Rating Scales by pencil and paper at the 6 and 12 month visits. Additional
NCAST and Bayley assessment results will be collected at 6 and 12 months corrected, scored and
subsequently entered by the RA into the database. Although no Spanish version of Bayley Scales is available,
previous research has shown that is sufficient that a Spanish fluent therapist who is trained can be used in
validated assessments.
49
Additionally, at the 6 and 12 month infant developmental ages for this study,
extensive language is not needed to accomplish the items; all other study instruments will be translated into
Spanish to facilitate capturing the two predominant language groups in Los Angeles. Each family will be given
a gift certificate of $30 for each visit in addition to access to free parking and a complimentary meal in the
hospital cafeteria. The KL2 pilot study determined that the measures should add an additional 45 minutes to
the regular clinical visit. NCAST and Bayley assessors will be masked to caregiver distress and infant history,
except for gestational age and birthdate that will be used to schedule appointments.
C2. General Approach to Data Analysis. The analytic plan consists of: a) descriptive analyses; b)
psychometric analyses of measures and scales to be constructed; c) multiple linear and logistic regression
models; and d) secondary path analyses to assess mediation. IBM SPSS Statistics (version 22) and Mplus
(version 7) will be used for data management and all preliminary and formal analytic activities.
Procedures to clean and screen survey data will include univariate analyses, patterns of correlation and
covariance, and checks for multicollinearity and singularity to facilitate the identification of multivariate outliers
and to check assumptions of multivariate normality (e.g., normal distribution, linearity, and homoscedasticity).
Variables will be transformed as needed to reduce the effects of valid outliers or violations of multivariate
normality. Univariate statistics will be used to examine the sample characteristics obtained at each time point.
Cross-sectional bivariate analyses, such as correlation analyses, t-tests, and chi-square tests, will examine
relationships among variables of interest. We will construct ranges and categorize data within each range as
appropriate for descriptive purposes. We will produce summary scores and scales of constructs of interest.
Scale scores will be created as means or sums of unweighted composite scores depending on original item
types (sums or percentages of checklist items). Psychometric properties (Cronbach’s alpha) of all measures
will be evaluated at each time point to ensure appropriateness for inclusion in more complex analyses.
Components of the conceptual model will be tested as described under each of the Specific Aims. Multivariate
analyses, such as linear regression modeling, will be used to determine the relative importance of biological
and environmental risk factors, and to test the time-lagged and concurrent effects of parental mental health on
the 6-month outcomes. Regression models will also be used to test the mediation hypotheses. Due to the large
number of potential covariates for use in the models, preliminary analyses will be run with and without the
covariate of interest in the model, and retained if they have a significant effect on the key outcome and/or
change the coefficient by more than 5%. We will also conduct missing data analyses in order to differentiate
between data that are missing at random (MAR) and data that may be missing due to selection bias or other
systematic effects. If missing data can be regarded as missing at random (MAR), multiple imputation may be
used. If the MAR assumption is not plausible, sensitivity analyses will be conducted to evaluate the impact of
MAR violations on analyses by specifying models for non-ignorable missing data mechanisms.
C2.1. Specific Aim 1: Investigate the delayed effects of caregiver traumatic stress from the NICU on the
neurodevelopmental outcomes of HRI. Hypothesis 1: Controlling for medical severity, greater caregiver
traumatic stress at 2 and 6 months will be associated with lower infant neurodevelopmental scores at 6 and 12
months, respectively.
A series of linear regression models will be tested in which caregiver depressive symptoms (CES-D score) and
traumatic stress (PPQ score) will be modeled as simultaneous predictors of total Bayley scores and subscale
composite scores. Cross-lagged models will use 2-month caregiver measures to predict 6- and 12-month
outcomes, and 6-month caregiver measures to predict 12-month outcomes. In all models, CES-D and PPQ will
be examined for multicollinearity. If multicollinearity is detected (zero-order correlations > 0.90 and/or variance
inflation factors > 5), alternate measures of caregiver traumatic stress, including the DTS, TEQ, or PSS:NICU
will be considered as a replacement.
C2.2. Specific Aim 2: Assess the concurrent effects of caregiver traumatic stress symptoms from the NICU on
the neurodevelopmental outcomes of HRI. Hypothesis 2: Controlling for medical severity and prior caregiver
traumatic stress, greater caregiver traumatic stress at 6 and 12 months will be associated with lower infant
neurodevelopmental scores at those same visits.
13

Concurrent models will use 6-month caregiver psychological measures to predict 6-month infant
neurodevelopmental outcomes and 12-month caregiver measures to predict 12-month infant outcomes. The
effects of biological insult defined by medical severity on caregiver traumatic stress symptoms (PPQ score,
continuous) will be examined via logistic and linear regression models, respectively. Initial models for each
outcome will consider medical severity, operationalized as the SNAPPE-II score and radiological imaging
findings (ordinal), as the primary predictor variables. Subsequent models may include other covariates
identified in preliminary analyses, such as age, race, ethnicity, primary language, country of birth, education
level, income, number of children, marital status, and/or previous NICU admission.
C2.3. Specific Aim 3: Evaluate whether caregiver traumatic stress and its effects on the caregiving
environment at least partially explain the persistent effects of medical severity on HRI neurodevelopmental
outcomes. Hypothesis 3A: Caregiver traumatic stress will partially mediate the relationship between medical
severity and infant neurodevelopmental outcomes; Hypothesis 3B: Quality of the infant-caregiver interaction
will fully mediate the relationship between caregiver traumatic stress and infant neurodevelopmental outcomes
proposed in Hypothesis 2.
Hypotheses 3A and 3B will be tested by following the steps to construct and test the Sobel product of
coefficients in a multiple regression framework. For Hypothesis 3A, the alpha coefficient corresponds to the
effect of medical severity on PPQ score (obtained in the analysis for Hypothesis 1A); the beta coefficient
corresponds to the effect of PPQ on total Bayley score (as in Hypothesis 2), controlling for medical severity.
For Hypothesis 3B, the a coefficient corresponds to the effect of caregiver traumatic stress on relationship
interaction quality, as measured by the NCATS; the b coefficient corresponds to the effect of interaction quality
on total Bayley score, controlling for PPQ score. In each case, a significant Sobel test of the product a*b would
indicate significant mediation effects.
Secondary Analyses. Secondary analyses will employ path analysis within a structural equation modeling
(SEM) framework in order to estimate the direct and indirect effects of all hypothesized predictors. Mediation
will be assessed by the significance of indirect effects. The analytic model predicting neurodevelopmental
outcomes will include measures of medical severity, brain injury, caregiver depressive and traumatic stress
symptoms, and relationship interaction. The SEM approach will allow us to test the plausibility of the overall
model or parts thereof, and evaluate the relative importance of the proposed causal relationships.
Group clustering effects. The conceptual model and the analyses it generates explicitly assume that the
proposed processes of neurodevelopment (i.e., via brain injury and caregiver mental health and interaction)
apply comparably to all NICU survivors, and that any systematic variation in outcomes based on the infant’s
diagnosis or subsequent medical intervention can be attributed to medical severity. Thus, we do not anticipate
substantial group differences based on study entry criteria. To verify this, codes representing each participant’s
diagnostic group and the intensive intervention received will be included in the data, and the diagnosis-group
and intervention-group intraclass correlations for each outcome will be calculated prior to conducting
regression analyses. If, as anticipated, no significant variance is accounted for by these groups, we will reduce
the model to a traditional one-level regression model. If significant group-level variance does emerge, alternate
options to enhance statistical power, including the use of diagnosis- or intervention-related dummy codes,
introduction of interaction terms, or multilevel regression models (families nested within diagnosis or
intervention groups) will be considered.
C2.4. Power Analysis to Determine Sample Size. The most novel contribution of the proposed study is to
establish evidence of a direct relationship between caregiver mental health and infant neurodevelopment
(Hypothesis 2). Therefore, we conducted a power analysis to ensure adequate statistical power to fully test this
hypothesis. Preliminary data obtained during the PI’s KL2 Career Development Award investigating survivors
of twin-twin transfusion syndrome suggested that concurrent parental stress explains 7.4% of the variation in
two-year neurodevelopment; this corresponds to a regression effect size of f
2
=0.08. Using G*Power v. 3.1.3
with f
2
=0.08, =0.05, adequate power (0.80), 2 focal predictors (caregiver CES-D and PPQ score), and 2-10
total predictors in the model to account for potential covariates, a sample of 125 families would provide
adequate power to test Hypothesis 2. Although our sample size is naturally limited by the number of patients
with intensive interventions seen in the CHLA NICU over the 3-year recruitment period, a sample of 125
intensive intervention infant cases would be feasible to identify, recruit, and follow in this setting. This sample
will also provide sufficient power to test Hypothesis 1A and 1B. Furthermore, we may have adequate power to
demonstrate significant mediation as proposed in Hypotheses 3A and 3B if the resulting regression coefficients
for each path are at least small to moderate (both coefficients ≥ 0.26 and at least one ≥ 0.39).
67

14

We do not expect to have enough power to fully test the proposed conceptual model within an SEM framework
in this K23 pilot study (see Secondary Analyses). However, enough data will be collected to serve as an
excellent training dataset for the PI to develop skills in regression, path analysis, and SEM approaches, and as
preliminary data for the planned R01 study that will have a larger sample size with sufficient power to detect
small mediated effects as well as account for any shared variance at the group level. In order to attain the
proposed final sample of 125 participants, 150 participants will be recruited to account for an up to 15%
attrition rate between consent and the 12-month follow-up period. Over 140 new patients are seen each year in
our HRIF follow-up clinic, with an average of 8 patients seen weekly. A 3-year study timeline is feasible based
on the clinical patient flow rate and previously piloted recruitment.
D. Potential Limitations, Alternative Strategies. The critical potential limitation of the study is the fixed small
pool of subjects available for recruitment. Our strategy to address this issue is to co-locate research personnel
in the CHLA HRIF clinic, integrate the clinical and research program for follow-up, and perform diverse
sampling across diagnostic and intervention groups. Additionally, participant retention could be an issue. The
clinic had a 10% loss to follow-up rate from the 6-month to 12-month visit. This will be addressed with
oversampling recruitment by 15%. This retention rate will be monitored closely with our tracking database.
Another potential issue is the generalizability of the unique medical severity, diagnostic and intensive
intervention features of the CHLA NICU population. The loss to follow-up could impact the generalizability if
more or less severe subjects have differential retention rate; thus, we will examine whether loss to follow-up
occurs with different rates among subgroups within the cohort (e.g., racial/ethnic groups, NICU intervention
type). Care should be taken not to assume that the findings could be generalized to primary or secondary
NICUs in which more less intensive interventions are performed. While all HRI will have experienced intensive
intervention and potentially traumatic stress event, naturally occurring medical severity heterogeneity could
have disparate neurodevelopmental outcomes that could obscure our mediation pathway. The data analysis
plan includes investigation of group effects, which is designed to mitigate this potential issue. The ethnic and
income differences seen in Los Angeles may also play a role in the findings. We will assess the demographic
diversity effects by testing them for potential inclusion as covariates in the regression model. Finally, infants
who are still in the NICU at 2 or 6 months corrected will not be eligible for the study, which will limit our
assessment of the most severely medically impaired children. This group would still be actively exposed to the
NICU stress event and therefore would not be appropriate for a study on the impact of persistent traumatic
stress sequelae on infant outcomes.
E. Timeline, Subsequent Studies, and Future Directions. The data generated from this study will provide
sufficient data to support an R01 application in order to fund a fully-powered outcome study investigating the
full conceptual model simultaneously describing caregiver mental health effects on HRI neurodevelopmental
and behavioral outcomes. A priority will also be to extend the longitudinal cohort to 2 years to assess the
relative impact of perinatal and relational risks at this critical time point. In this future grant, I will explore the
use of machine learning algorithms to create prediction models and advanced imaging methodologies such as
surfaced-based analysis. This K23 proposal will support my career development into an independently funded
clinical researcher and national leader in the area of contextual HRI neurodevelopmental follow-up. Through
refinement of this comprehensive process model that simultaneously includes medical, caregiver, and
relationship factors, I will have a firm theoretical foundation from which successful interventions can be
designed and tested.
Table 1. Timeline of Planned Activities
Year 1 Year 2 Year 3
Quarters Quarters Quarters

1 2 3 4 1 2 3 4 1 2 3 4
CAREER DEVELOPMENT (40% effort)

Courses- 15%

Theories of Human Behavior in the Contexts of Social Environments (Fall)

Research Design in Developmental Psychology (Spring)

Advanced Overview of Neurosciences (Fall)

Advances in Neurodevelopmental Disorders (Spring)

Seminar in Social Psychology (Fall)

Design of Clinical Studies (Spring)

Directed Readings & Tutorial with Mentors- 10%

Institutional Seminars/Workshops/Meetings- 5%

15

Responsible Conduct of Research Courses

Manuscript Submissions- 10%

RESEARCH PROJECT (35% effort)

Complete IRB Approval

Recruitment and 2 month corrected assessment

6-month corrected assessment

12-month corrected assessment

Data analysis

Publication of data

R01 submission

CLINICAL/ADMINISTRATIVE ACTIVITY (25% effort)

Targeted-Planned Enrollment

Total Planned Enrollment: 150 infants and 150 caregivers (recruited as dyads)
Racial Categories Not Hispanic Hispanic Total
Female Male Female Male
American Indian/Alaska Native 0 0 0 0 0
Asian 25 9 0 0 34
Native Hawaiian or Other Pacific Islander 2 0 2 0 4
Black or African American 25 9 0 0 34
White 46 16 120 42 224
More Than One Race 2 0 2 0 4
Racial Categories: Total of All Subjects
*
100 34 124 42 300
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial
Categories: Total of All Subjects.”

16

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19

Candidate’s Background
I am deeply committed to understanding and improving the lives of high risk infants (HRI), and I
firmly believe that research is the key to shifting HRI life course to a more favorable trajectory.
Before I can develop successful preventive interventions for these vulnerable infants and their
caregivers, I must develop a deeper understanding of the critical relationships between medical
and psychological risk factors. My interest in HRI began when I was only five years old, when I
helped deliver my brother after my mother went into labor at home 35 weeks into her pregnancy.
Nurturing my brother through his life, I witnessed both the subtle developmental challenges
common to late-preterm children and the powerful protective effects of family support. Psychology courses in
high school and college gave me the conceptual framework to understand the interrelation between perinatal
risks and protective factors that I had lived firsthand. A career in medicine provided me with opportunity to
understand the biological origins of development and behavior. Throughout medical school and pediatric
residency, I have sought every opportunity to study the physical and mental health of infants and children.
I pursued a fellowship in Developmental-Behavioral Pediatrics (DBP) at Boston University based on their
reputation for rigorous research in this transdisciplinary field that unifies medicine and psychology to evaluate
and treat children with behavioral and developmental disorders. During my DBP fellowship, I developed a
strong interest in research methodology and recognized the potential of research to improve the life course
trajectories of HRI. Under the supervision of Dr. Deborah Frank (see letter of reference), my early work
focusing on the interrelationship of post-traumatic stress disorder (PTSD) symptoms with physical health
symptoms in children with asthma was published in the Journal of Trauma and Dissociation (Appendix 1). In
my Boston University faculty position, I was awarded a Zero To Three Fellowship to develop a HRI follow-up
clinic, giving me a prime opportunity to create an environment supporting infant mental health research. I
focused on the prevalence of PTSD symptoms among caregivers with infants who have been in the NICU.
These data have been published in the Journal of Developmental and Behavioral Pediatrics, again under the
mentorship of Dr. Frank (Appendix 2).
I was recruited to the University of Southern California (USC) and Children’s Hospital Los Angeles (CHLA)
on the basis of my clinical research leadership potential. Here, I have continued to investigate the relationships
between caregiver stress and developmental outcomes in the HRI population. Under the mentorship of Dr.
Istvan Seri in Neonatology, I obtained The Saban Research Institute (TSRI) Mentored Junior Faculty Clinical
Research Academic Career Development Award in July 2009, evaluating the role of caregiver stress in
neurodevelopmental outcomes of 2-year-old survivors of twin-twin transfusion syndrome. My presentations of
these data have earned awards from the Association for Clinical Research Training and Society for Clinical
and Translational Science, the Southern California Clinical and Translational Science Institute (SC-CTSI), and
TSRI. These early experiences provided me with the foundation for a research career in academic medicine.
In recognition of my early successes, the SC-CTSI awarded me a Mentored Career Development KL2 award
in 2011 to support pilot and feasibility testing of NICU-based HRI recruitment. The KL2 has been critical to
developing and evaluating the sustainibility of the participant recruitment, retention, and measurement
strategies that informed this application. As part of the KL2 program, I have begun formal research methods
coursework toward a Master of Science degree in Clinical and Biomedical Investigations. This dedicated time
has also allowed me to expand my understanding of the literatures relevant to my proposed conceptual model
and increased my ability to publish (Appendix 3). In recognition of my excellence in medical education, I was
recently promoted to Associate Professor of Clinical Pediatrics; however, despite being nine years into my
acadmeic career, I am still lacking the necessary theoretical framework, grounding in core concepts of social
interaction and neuroscience, and knowledge of sophisticated assessment and analytic methodologies that
would make me competitive for funding at the R01 level.
Clinical work changes one child at a time and medical education changes one practitioner at a time, but
research has the potential to change the entire field. In order to reach my academic career goals of
establishing a sustainable HRI research program and obtaining independent funding, I have used my KL2 to
shift focus from clinical and administrative training roles by identifying and connecting with essential mentors
who will provide me research training in the multiple disciplines united by my research. The K23 award will
provide the dedicated research time needed to refine my conceptual model and acquire preliminary data on the
mechanisms underlying HRI neurodevelopment. At the end of these 3 years, I will be prepared to propose a
fully powered, theoretically informed R01 trial of an intervention to be chosen based on the mechanisms
determined during the K23. Data collected during the R01 will also support fully testing the conceptual model in
a methodologically rigorous framework. To ensure my success, the Department of Pediatrics has committed to
support 75% of my time for research and career development activities for the entire duration of the K23.
20

Career Development Goals
Despite my recent academic promotion, which was based on success in obtaining Health Services Research
Administration-Maternal Child and Health Bureau training grants, my research expertise has several critical
gaps relative to my career goals. In order to be successful at improving the lives of high risk infants (HRI), I
need a firmer grounding in theoretical psychology in both developmental systems and interpersonal social
psychology. To become an independent research scientist, I need to obtain a deeper understanding of content
knowledge and assessment modalities of medical risks to development in areas of neonatology and
neuroimaging. A successful R01 application will also require proficiency in longitudinal research methodology
and analysis in addition to specialized assessment skills.
My career goal is to become a national leader in the neurodevelopmental course of HRI and interventions to
improve outcomes. The K23 award will provide essential opportunities to gain knowledge and practical
experience in conducting rigorous research with HRI and their families. There is currently a lack of a
comprehensive understanding of the developmental effects of caregiver traumatic stress on these medically
vulnerable infants. Remarkable innovations have occurred in the technology-driven medical aspects of the
care of these high risk infants (HRI), but without the complementary and necessary additional focus on
improving the caregiving environment in which these infants develop. Understanding the interplay between
infant medical severity and the infant-caregiver relationship has the greatest hope for improving
neurodevelopmental outcomes. Thus, this field has great potential for my career development. Future
interventions based on my proposed work could consist of robust screening protocols and psychological based
therapies with caregivers and/or developmental enrichment and rehabilitative therapies with the infants. I am
strongly committed to addressing this gap between biology and psychology through my academic career, and
the K23 award provides the framework to develop into an independent physician-scientist.
To meet my overall goal, I will convene a multidisciplinary team to study the complex relationships of
biological injury and family context on outcomes for HRI. Since 2011, the KL2 Career Development Award has
provided me with the opportunity to establish productive mentoring relationships with experts in cognitive
neuroimaging, physics, neonatology, psychology, social work, and pediatrics. The KL2 has allowed me to
begin formal research training through introductory translational science and biostatistics coursework toward a
Master’s of Science degree in Clinical and Biomedical Investigations at USC as well as bi-weekly seminars
with mid-level and senior investigators focused on clinical-translational research and career development. I
have also been able to assess the feasibility of engaging a post-NICU cohort and pilot the assessment of
relationship factors in another HRI sample. Through this preliminary work, I have identified specific areas of
skill and knowledge in patient-oriented research that, once acquired, will position me to compete successfully
for independent R01 funding. Thus, my short term goals to address my current career development gaps are:

1. Apply developmental systems and infant mental health theories to HRI neurodevelopment;
2. Develop a theoretical understanding of the role of biomedical and psychological factors in HRI
neurodevelopment;
3. Acquire skills in relationship assessment and modeling methodologies;
4. Develop expertise in longitudinal cohort designs, management of multidisciplinary research teams,
and multivariable methods appropriate for longitudinal data.
My progress on these goals will be overseen through three levels of mentorship. My primary mentor (Istvan
Seri, MD, PhD), has extensive experience with clinical research involving neonates and will be my navigator
for patient-oriented scientific career development. I have also constructed a content mentorship team to
address my knowledge in intergenerational traumatic stress outcomes (Penelope Trickett, PhD), research
methodology and career mentorship (Jonathan Samet, MD), toxic stress to infant development (Pat Levitt,
PhD), and psychological research design and analysis (Sheree Schrager, PhD, MS). I will also seek
consultant guidance in applying the research to clinical neurodevelopmental outcomes in HRI (Kathleen
Nelson, MD) and understanding biological injury assessment through neuroimaging (Natasha Lepore, PhD).
All members of my mentorship team have competed successfully for NIH funding as PI or have been part of
NIH funded studies. The table below lists my career goals and the mentors who will oversee them.
Career Goals Mentor / (Consultant) Mentor Contact Plan
1. Developmental systems/infant mental health theory Trickett / Levitt Weekly lab meetings / Quarterly
2. Biomedical and psychosocial factors Seri / Trickett / (Lepore) Biweekly / Weekly lab meetings
3. Dyadic assessment/modeling methodologies Schrager / (Nelson) Weekly
4. Research design, management and analysis Schrager / Samet Weekly / Quarterly
5. All goals and overall career development Seri / Samet Biweekly / Quarterly

21

Career Development Activities During Award
My career development plan leverages interdisciplinary mentors and activities from the University of Southern
California Schools of Social Work, Engineering, and Medicine, Department of Psychology, and Neuroscience
Program. In consultation with my mentors, I have identified formal graduate level coursework to complete a
Master of Science degree in Clinical and Biomedical Investigations in the Department of Preventive Medicine,
practical training in multidisciplinary areas, and mentored research opportunities in accomplishing my career
goals to:
A. Apply developmental systems and infant mental health theories to HRI neurodevelopment.
Rationale: I have been trained as a developmental-behavioral pediatrician to clinically assess and treat the
medical and psychological origins of children’s developmental and behavioral disorders; however, I need
formal research training in the application of explanatory model-driven studies to developmental outcomes.
This social science-based expertise is critical to successfully identifying relevant medical and psychological risk
and protective factors that can enhance caregiver functioning and infant outcomes. Having a clearer
understanding of these risk factors within a theoretically-grounded conceptual framework, will support
development of promising NICU-based and post-NICU interventions to address infant outcomes beyond
technology-driven medical treatments.
Coursework: Theories of Human Behavior in the Contexts of Social Environments (3 units, Social Work, Dr.
Barrio): This course focuses on human behavior in interaction with the social environment including general
systems theory, social ecological model, and role theories. Seminar in Social Psychology (4 units, Psychology,
various faculty): This course explores the problems and theories of the person in the social context including
person perception, interpersonal relations, attitude dynamics, and social systems.
Research Application: I will apply this knowledge to the refinement of my conceptual model and the selection
of measurement variables intended to capture the modifiable environmental risk factors for infant development.
I will supervise relationship, mental health and developmental assessments during data collection and
construction of potential interventions.
Mentor Tutorials: Dr. Trickett will provide content mentorship on the effects of caregiver traumatic stress on
infants through discussions at her monthly research cluster meetings and weekly lab meetings. She will
provide me with directed readings, manuscript opportunities and collaborative discussions on assessment
methodology and content mentorship. Dr. Levitt will provide quarterly meetings on toxic stress in infant
development. Dr. Nelson, my consultant, will guide the conceptual model testing with monthly HRI clinic
meetings.
B. Develop a theoretical understanding of biomedical/psychological factors in HRI neurodevelopment.
Rationale: In addition to the proposed relationship process model, the traditional direct pathway in my
conceptual framework describes the influence of infant medical severity on developmental outcomes. I need to
build knowledge of the interrelationship of the biomedical and psychological factors in explaining infant
neurodevelopment, including the use of neuroimaging to define infant medical severity. Full delineation of the
medical and psychological risks for neurodevelopment will require a firm grounding in the processes of healing
after brain injury and the caregiver sequelae that may also follow.
Course work: Advanced Overview of Neurosciences (4 units, Neuroscience, Dr. Levitt): Study of the nervous
system at multiple levels through the analysis of four themes: Motor Control; Emotion, Motivation, and
Decision-Making; Memory and Learning; and Vision. Advances in Neurodevelopmental Disorders (2 units,
Neuroscience, Dr. Levitt): Classic and current readings and discussion of genetic and experienced based
factors that lead to disrupted brain and child development.
Workshop: I will attend the monthly USC Cognitive Neuroscience and Neuroimaging Journal Club (Wed 2-
3PM) to become current on the recent topics in cognitive neuroscience and the methods used to implement
this research. The goal of the journal club is to interact with researchers experienced in structural and
functional imaging analysis techniques. Dr. Levitt’s courses will provide the background for this workshop.
Research application: I will use perinatal risk factors and clinical neuroimaging to capture the key variables of
infant medical severity. Dr. Lepore will assist in analyzing the neuroimaging results.
Mentor Tutorials: Dr. Seri will provide primary mentorship on contextualizing the impact of medical severity
and value of neuroimaging in defining the biological injury. Dr. Lepore will consult on neuroimaging technique
application and analysis of these modalities to define medical severity and its sequelae on a monthly basis.
C. Acquire skills in relationship assessment and modeling methodologies.
Rationale: In my clinical work, I have used the Bayley Scales and caregiver mental health screening tools to
identify developmental and behavioral problems in infants and children. However, I lack a sophisticated
methodological understanding of the theoretical construction and application of different measures of cognitive,
22

social and emotional development in HRI and caregiver measures of psychological distress. Understanding the
rigorous use of psychometrically validated research tools to define caregiver and infant outcomes is essential
to predicting future neurodevelopmental problems.
Workshop: NCAST PCI Instructor Workshop is a 6-day intensive workshop in Seattle, WA (March, 2015): This
highly regarded workshop will provide additional understanding and training in administering and coding the
NCAST feeding and teaching subscales. I will attend the Bayley Scales Web Seminar, developed by the
publisher to provide the necessary expertise to use the Bayley tool and to recognize its strengths and
weaknesses.
Research application: These standardized assessment tools are key predictors of outcomes in this research
project. I will develop a thorough understanding of the theoretical rationale, administration, and analytic
strengths and limitations of these measures during the conduct of the proposed research.
Mentor Tutorials: Dr. Trickett has extensive experience using these tools in her research projects, and I will
learn from her supervision of my project in the weekly research group meetings. Dr. Nelson has been a
member of the NICHD NICU follow-up research network and will provide consultation monthly in the HRI follow
up clinic to provide guidance on operationalizing the project in this setting.
D. Develop expertise in longitudinal cohort designs, management of multidisciplinary research teams,
and multivariable methods appropriate for longitudinal data.
Rationale: As a KL2 scholar under Dr. Jonathan Samet’s supervision, I have received basic research training
in statistical techniques and research designs appropriate for simple biomedical studies. I need formal
mentorship and coursework in more advanced research methods to manage the integration of medical and
psychological variables in longitudinal, theoretically informed studies of HRI.
Course work: Research Design in Developmental Psychology (4 units, Psychology, Dr. McArdle): Review and
practice in the analysis and design of experimental and quasi-experimental paradigms for research on
ontogenetic age changes and generational differences in behavior.
Workshop: Design of Clinical Studies (3 units, Preventive Medicine, Dr. Patino-Sutton) Design, conduct, and
interpretation of results of clinical trials; emphasis on principles affecting structure, size, duration of a trial, and
the impact of ethical and practical considerations. Additionally, I will acquire training in the ethical principles of
research as outlined in section Training in Responsible Conduct of Research.
Research application: As study Principal Investigator, I will be responsible for all aspects of the study
including design, recruitment, implementation, and data collection, management, analysis, and dissemination. I
will work closely with content mentor Dr. Sheree Schrager to carry out the proposed analyses. Knowledge
gained from this methodological training will support me to carry out all aspects of the proposed K23 project as
well as to develop a methodologically strong approach to the subsequent independent R01 study.
Mentor Tutorials: Dr. Seri will closely mentor me on my effective implementation of this career goal with twice
a month sessions. Dr. Trickett complements Dr. Seri’s mentorship with her work with a longitudinal cohort of
traumatized women and their children. She will mentor me on the cohort recruitment and tracking and the
assessment and analysis of psychometric data. Dr. Samet will provide in depth career mentorship and specific
expertise in research methodology. Dr. Schrager has extensive experience in the management and analysis of
NIH-funded studies, including sophisticated longitudinal analysis methods, and will meet with me weekly for
guidance in study management procedures (Years 1 and 2) and advanced statistical methods including
multiple group modeling and structural equation modeling in Mplus (Year 3).
Seminars and Scientific Meetings: In addition to formal coursework and research application, I will continue
to promote my career development by participating in the Southern California-CTSI seminars, which focus on
current updates in research methodologies, interaction with the leaders of clinical research at USC, and
presentation of my research for peer and mentor review. I will also present my research in national forums via
abstract submissions to the meetings of the Pediatric Academic Societies, Society for Developmental and
Behavioral Pediatrics, International Society on Infant Studies, and Society for Research in Child Development.
Coordinated Mentorship Plan: The mentorship plan, overseen by the Dr. Seri as the primary mentor, is
designed to ensure that the mentorship is well-coordinated and that I will successfully complete the research
training and productivity benchmarks proposed in this award. It calls for (1) twice-monthly formal meetings with
Dr. Seri to discuss research and training progress, plus informal meetings as needed; (2) individual meetings
at least weekly with co-mentor Drs. Trickett and Schrager, and quarterly with Drs. Samet and Levitt; (3)
individual meetings at least monthly with my consultants Drs. Nelson and Lepore; and (4) meetings at least
quarterly with the core mentorship committee comprised of Drs. Seri, Trickett, Samet, and Schrager. Please
see mentor letters for the formal monitoring plan to assess progress toward meeting of benchmarks outlined in
the research and career development plans and Table 1 in Research Strategy for a timeline of activities.
23

Table 1. Timeline of Planned Activities
Year 1 Year 2 Year 3
Quarters Quarters Quarters

1 2 3 4 1 2 3 4 1 2 3 4
CAREER DEVELOPMENT (40% effort)

Courses- 15%

Theories of Human Behavior in the Contexts of Social Environments (Fall)

Research Design in Developmental Psychology (Spring)

Advanced Overview of Neurosciences (Fall)

Advances in Neurodevelopmental Disorders (Spring)

Seminar in Social Psychology (Fall)

Design of Clinical Studies (Spring)

Directed Readings & Tutorial with Mentors- 10%

Institutional Seminars/Workshops/Meetings- 5%

Responsible Conduct of Research Courses

Manuscript Submissions- 10%

RESEARCH PROJECT (35% effort)

Complete IRB Approval

Recruitment and 2 month corrected assessment

6-month corrected assessment

12-month corrected assessment

Data analysis

Publication of data

R01 submission

CLINICAL/ADMINISTRATIVE ACTIVITY (25% effort)

24

Training in the Responsible Conduct of Research
I have completed the Responsible Conduct of Research (RCR) online basic course for the biomedical sciences
offered by the Collaborative Institutional Training Initiative (CITI) Program, which includes the following
modules: Research Misconduct; Data Acquisition and Management; Sharing and Ownership; Publication
Practices and Responsible Authorship; Peer Review; Mentor and Trainee Responsibilities; Conflicts of Interest
and Commitment; Collaborative Research; Human Subjects. I also recently completed a refresher course
specifically for the social and behavioral sciences which includes the following modules: Defining Research
with Human Subjects, The Regulations and The Social and Behavioral Sciences, Assessing Risk in Social and
Behavioral Sciences, Informed Consent, Privacy and Confidentiality, Research with Prisoners, and HIPAA and
Human Subjects Research. Additionally, I have completed the CITI Good Clinical Practice course, which
included modules on New Drug and Device Development, Belmont Report, ICH and FDA Regulation
Overview, Conducting Clinical Trials, Detecting and Reporting Adverse Events, and Auditing Requirements. I
have current certifications from the Institutional Review Board (IRB) at CHLA for Human Subjects, Good
Clinical Practice, and HIPAA. I am committed to conducting clinical research in a manner so that the ethical
rights of the human participants in my studies are protected. It will be important to ensure that caregivers do
not perceive enrollment strategies as coercive, particularly in the context of research led by their child’s
physician, and that they feel that the research methods respect their autonomy for decisions affecting them
and their child. Toward that goal, I have included additional study of ethical issues clinical research designs in
my career development plan under Goal 4 (Develop expertise in longitudinal cohort designs, management of
multidisciplinary research teams, and multivariable methods appropriate for longitudinal data).

Learning Objectives:
1. To learn about specific ethical issues that may occur in infant-caregiver relationship assessment and infant
neurodevelopmental outcomes research, mental health assessment research, and research involving high-risk
infants and stressed mothers.
2. To develop knowledge and skills of best practices to address ethical issues for these types of research.

Mentors: Drs. Istvan Seri, Jonathan Samet, and Sheree Schrager will provide mentorship for this goal.
Activities:
1. I will ensure that all members of my research team have completed the required Human Subjects
Protections certifications through the CITI program, satisfying IRB requirements for Human Subjects, Good
Clinical Practice and HIPAA certifications. This certification and training will need to be updated in Year 3
for myself (6-8 hours).

2. As a K23 Awardee, I will attend a more extensive 5-day workshop course at USC Keck School of Medicine
on Responsible Conduct of Research (INTD 500), offered each summer. Lecture and discussion topics
include: scientific integrity, misconduct and fraud in science, data acquisition and management, collaborative
research, responsible authorship, conflicts of interest, innovation advancement and patents, animal welfare,
human subjects, mentor-mentee responsibilities, and professionalism in scientific relationships. This course is
designed to meet the educational requirements in scientific integrity and the responsible conduct of research
as per the Update on the Requirement for Instruction in the Responsible Conduct of Research (NOT-OD-10-
019). The director, Dr. Donna Spruijt-Metz, is a presenter at Southern California Clinical & Translational
Science Institute (SC-CTSI) Education, Career Development, and Ethics (ECDE) sponsored K Scholar
seminars, and conducts ongoing clinical research ethics forums in conjunction with the SC-CTSI and the
Pacific Center for Health Policy and Ethics at USC (10 hours).

3. The Responsible Conduct of Research Training course at CHLA provides researchers with educational
requirements in scientific integrity and the responsible conduct of research as per the National Institutes of
Health (NIH). The course runs six Thursday mornings in the Spring semester.

4. My primary and secondary mentors will oversee my progress in responsible conduct of research in our
mentorship meetings. They will ensure that I complete the Responsible Conduct of Research course at USC,
and maintain competencies in Human Subjects and GCP Certifications through CHLA. I will also consult with
my Mentoring Team to answer questions related to the responsible conduct of research as they arise. Dr.
Schrager is a member of CHLA’s IRB and will be available to discuss ethical issues or concerns during our
planned weekly meetings (see Career Development Activities).
25

Protection of Human Subjects
This Human Subjects Research meets the definition of Clinical Research.

A. Risks to Human Subjects
a. Human Subjects Involvement and Characteristics:
The proposed project will recruit term and preterm infants and their principal caregivers whom have been in a
neonatal intensive care unit (NICU). An anticipated number of 150 pairs will be enrolled in the study, based on
the following criteria. Infants are a vulnerable population and will be included to obtain data to assess the
proposed hypotheses on the developmental effects of caregiver traumatic stress from the NICU.
Inclusion: Infants who can be seen in the Children’s Hospital Los Angeles (CHLA) High-Risk Infant Follow
up(HRIF) clinic (i.e., all infants born less than 32 weeks and/or 1500 grams or having a potential
neurodevelopmental risk intensive intervention or condition as described in research strategy); have
experienced an intensive medical intervention (extracorporeal membrane oxygenation, circulatory support,
total body cooling, or ventilator support); are born alive and survive to follow-up; and have English- or Spanish-
speaking caregivers. Presenting primary caregivers must be the legal guardian of the infant being enrolled.
The caregivers must speak English or Spanish so that validated neurodevelopmental outcome assessment
tools may be used.

Exclusion: Patients will be excluded if they are unable to enroll in the HRIF clinic or if they received
interventions for congenital heart disease as their brain development in utero may be affected by the
underlying heart disease; this group of patients is qualitatively different from other NICU survivors and is
expected to have a different long-term neurodevelopmental outcome compared to neonates receiving
interventions for non-cardiac pathologies. Exclusion criteria also include major infant congenital or brain
abnormality, defined genetic syndrome, and caregivers unable to complete the follow-up visit or measures due
to cognitive limitations or language.

Patients are primarily referred to the HRIF clinic from NICU located at CHLA, Hollywood Presbyterian Medical
Center, Good Samaritan Hospital, and Los Angeles County at University of Southern California, and a small
percentage may be referred by other outlying NICU.

b. Source of Materials
The present application involves collecting data on perinatal risk factors of primary diagnosis and medical
severity from the medical record. Caregiver depression and posttraumatic stress symptoms will be collected at
2, 6, and 12 months in the HRIF clinic. Neurodevelopmental outcomes will be assessed using the Bayley
Scales of Infant Development-III at 6 and 12 months of age. IRB approval is pending.
c. Potential Research Risks: One of the primary risks of participation is that the research includes the risk of
disclosure that a participant may have engaged in self-harm or attempt suicide. All the Specific Aims
investigate the effects of NICU-related caregiver traumatic stress symptoms on the neurodevelopmental
outcomes of HRI, which necessitates collecting sensitive information about traumatic stress experiences.
Others risks may be that the questionnaires may make the participant feel uneasy or embarrassed or uncover
significant depressive, suicidal, or traumatic stress symptoms or that there is a possibility of a loss of
confidentiality for study participants. A number of precautions and safeguards developed by our team will be
used in this study in order to protect the confidentiality of individuals who participate in the study. Due to these
symptoms being both an outcome and predictor, it will be important to assess them in the course of the
research.

B. Adequacy of Protection Against Risks
a. Recruitment and Consent: On a weekly basis, the Principal Investigator (PI) will identify eligible potential
participants from those referred to the HRIF clinic for the initial 2-month corrected visit using patient information
in the electronic medical record or discharge summary. As required by the CHLA IRB, all members of the
research team, including the RA, will have completed training in human subjects’ research. The RA will contact
the caregiver prior to the HRIF clinic, by letter and phone, to explain the study. Recruitment tools will include a
26

telephone script as well as a verbal script for in-person recruitment. The RA will obtain consent at the initial 2
month visit.
As study visits will occur at 2, 6, and 12 months corrected age, the RA will coordinate all research visits with
the HRIF nurse coordinator. The RA will contact the caregiver prior to each research visit to preview what the
participants should expect regarding time and activities. If a caregiver needs a Spanish interpreter, the RA will
use the phone translation service that can be accessed the day of the appointment. Prior to each visit, the RA
will assemble the necessary materials, including HIPAA and consent documents as needed, and will have
access to a networked computer, paper measures, and incentives. The caregivers will be informed that refusal
to participate in the research study will not jeopardize the quality of medical care that they would continue to
receive from the physicians involved.

All individuals who agree to participate in the proposed study will need to provide formal informed consent. The
Institutional Review Board (IRB) at CHLA requires that all research participants review and sign an informed
consent form as well as a Human Subjects Bill of Rights form. The informed consent covers information about
the overall purpose of the study, a description of what the study entails, a statement disclosing potential risks,
potential benefits to participating individuals and society, a statement about the confidentiality of data, and
contact information for the Principal Investigator. Informed consent will be obtained in a private setting on the
day of the appointment prior to any other exam. Due to the age of the infants, caregivers will provide consent
for their and their infant’s participation but infant assent cannot be obtained. The informed consent process is
as follows:
1. Participants will be given a copy of the Experimental Subjects' Bill of Rights to read and sign before they
are given the study consent. Participants will be given a copy to keep. A form describing HIPAA will also be
given at the time of consent. Participants will be encouraged to ask any questions they may have.

2. The RA will obtain consent in-person and will also sign the study consent form to verify that proper consent
procedures were followed. Participants will be given a written copy of the study consent to read and sign;
they will also be given a photocopy of the signed consent form to keep.

3. Consent will be obtained in a language the participant can understand, with the use of a translator, if
necessary.

4. Consent will be documented by maintaining a copy of the consent form in the medical record, as well as
a copy in a locked file cabinet in the office of the PI.

b. Protection Against Risk:
The caregivers will be informed of the possible discomforts and risks associated with the study prior to their
participation. Caregivers who are uncomfortable with any portion of the study may decide not to participate.
1. All participants will be given the opportunity to withdraw from the study or modify its progression at any point.
Information about the study procedures and what to expect will be given at the time of initial contact and
initiation of the assessment. Care will be taken to reassure participants that their choice to participate or not
will in no way affect their child’s medical treatment at CHLA, so as to reduce the likelihood of coercion.
2. We will make our best effort to keep the findings in this study private. Research procedures will be
conducted in person in a private setting. Data will be captured and reviewed in a private setting. Only
authorized research study personnel will be present during research related activities. The collection of
information about participants is limited to the amount necessary to achieve aims of the research.
Participants will not be approached in a setting or location that may constitute an invasion of privacy or
could potentially stigmatize them. The initial contact will be in the CHLA’s HRIF clinic. If participants are
interested in hearing more, they will be able to discuss and sign consent forms in private room in the clinic.
3. The caregiver and infant participant codes will be generated in serial fashion based on order of recruitment.
The caregiver code will link with the infant code for data analysis, so that caregiver and infant data can be
connected without the use of names or other identifying information.
27

4. The use of a suicide SOP will mitigate the risk of identifying a suicidal caregiver. Participants can choose to
skip or stop answering any questions that make them uncomfortable. A trained research assistant under the
supervision of the PI will monitor participants during data collection sessions for signs of caregiver
posttraumatic stress, depression or suicidality. If suicidal ideation or behavior is disclosed, referrals to
qualified mental health professionals will be provided according to a standard operating procedure in place
to manage these potential findings and safeguard the infants and caregivers involved in the study.
5. To prevent against inappropriate use or disclosure, data will be coded and identity stored separate from
data. Consent forms, research protocols, completed measures and data sheets will be kept at CHLA and
will be stored in a locked cabinet in a locked office with restricted access to study personnel. Completed
measures and data sheets will be removed from the locked cabinet entered into the research database, and
returned. The research database will be coded and password-protected on a secure computer, with an
individual ID plus password protection, during and after the study. The codebook to the database will be
held on the PI's computer, which is also encrypted and password protected. All digital data will be encrypted
and hospital security software (firewall, antivirus, anti-intrusion) is installed and regularly updated in all
servers, workstations, laptops, and other devices.
C. Potential Benefits of Proposed Research to the subjects and others
There are no direct benefits to the research participants.

The overall benefit to society is that this study will advance knowledge. The potential benefits to humanity
justify exposure of the participants to the risks.

D. Importance of Knowledge to be Gained
Our overall aim is to examine the impact of NICU-related caregiver traumatic stress symptoms in order to
improve HRI outcomes. Studies of HRI outcomes published to date have typically considered medical risk
factors entirely separately from psychological risk factors such as caregiver traumatic stress and infant-
caregiver relationships; yet evidence from other preterm samples suggests that these are critical risk factors for
neurodevelopment and behavior. Specifically, the proposed research study will model the effects of caregiver
posttraumatic stress symptoms and the quality of infant-caregiver relationship, beyond the effects of medical
severity, on the neurodevelopmental outcomes of HRI. This study has the potential to improve outcomes for
this highly vulnerable population by documenting the interplay between medical and psychological risk factors,
which will prepare me to develop and test a fully powered, theoretically informed intervention based on the
mechanisms determined during this study.

28

Inclusion of Women and Minorities
Women and minorities will be included in this study. We plan to enroll 150 caregivers of infants regardless of
gender, race, or ethnic background. Based on our pilot study, we expect eligible caregivers to be
predominantly women. The racial/ethnic distribution of caregivers enrolled in this study is expected to match
the CHLA patient population. See the Targeted/Planned Enrollment Table for the combined caregiver and infant
estimated numbers in each gender and racial/ethnic group.

29

Inclusion of Children

This research project will recruit 150 infants at 2 months of age (corrected for gestational age) at baseline.
Those infants and their caregivers will be assessed at 2, 6 and 12 months corrected age. Children are a
necessary component of this study, which seeks to assess the neurodevelopmental outcomes of a medically
severe population of infants. Consent will be obtained from all caregivers on behalf of their infants. At the High
Risk Infant Follow-up (HRIF) clinic at Children’s Hospital Los Angeles, the clinicians and investigators
specialize in assessment of these medically severe infants and their stressed caregivers. The investigators
have extensive experience in conducting research with infants and caregivers. See the Targeted/Planned
Enrollment Table for the combined caregiver and infant estimated numbers in each gender and racial/ethnic
group.

30

Description of Institutional Environment
This Career Development Award will be pursued at Children’s Hospital Los Angeles (CHLA), the University
of Southern California (USC), and The Saban Research Institute (TSRI) at CHLA. The University of Southern
California (USC) offers an outstanding training environment for young researchers. USC has nearly $560
million in annual research expenditures, and has ranked among the top 10 private universities in federal
supported research activity. The Health Science Campus is home to the Keck School of Medicine and three
teaching hospitals. The USC-based Southern California Clinical and Translational Science Institute (SC CTSI),
which is funded by an NIH Clinical Translational Science Award, offers abundant educational and scientific
opportunities for Dr. Vanderbilt’s career development. This includes access to its coursework aimed at
physicians seeking a Master of Science degree in Clinical and Biomedical Investigation and its wide array of
core resources. Additionally, the proposed study will be carried out within the High Risk Infant Follow-up
(HRIF) Clinic at CHLA, where Dr. Vanderbilt routinely sees patients as well as conducting his KL2 investigator-
initiated feasibility study over the last two years. This clinic is overseen by his primary mentor, Dr. Seri, who is
the director of the Center for Neonatal and Fetal Medicine at CHLA/USC; Dr. Seri also directs the primary
referral site for patients for the HRIF clinic. Dr. Vanderbilt will also participate as a member of the Child
Development Research Core of the School of Social Work, which is directed by his co-mentor, Dr. Trickett.
This Research Core provides a community of scientists from throughout USC who will support this project
along with his career development. His mentorship team involves an innovative cross-disciplinary collaboration
among scientists from multiple departments and divisions at CHLA/USC, including Neonatology,
Developmental-Behavioral Pediatrics, Radiology and Clinical Imaging, Preventive Medicine, Hospital Medicine,
the USC School of Social Work, and the SC CTSI, and he will thereby have access to resources within their
respective divisions.
As a faculty member in the Department of Pediatrics, Dr. Vanderbilt also has access to physical and
intellectual resources at USC and CHLA (see Facilities and Other Resources) that will allow him to
successfully complete the aims outlined in this proposal and to obtain the didactic training and mentored
research experience to help him become an independently funded clinician-scientist. The Department of
Pediatrics holds a NICD Child Health Research Career Development Award (K12) (PI, D. Brent Polk, MD) to
provide supervised research training and mentoring to assist the transition into productive physician scientists
in areas related to pediatrics and its subspecialties. CHLA and TSRI support The Donnell Society, which trains
pediatric scientists to perform innovative and high-quality research. The Society provides mentorship,
infrastructure and a community for pediatric scientists in training. Activities include invited physician scientist
speakers, chalk talks, educational activities, mixers, social events, offsite educational opportunities and
administrative support including, grant preparation, manuscript submission, society memberships, license
renewal and certifications. TSRI also hosts a weekly research seminar series, with lunch provided. The
Research Seminar series is intended for our scientists to learn about exciting new scientific developments
important to our research community. Graduate students, research and clinical fellows as well as faculty
members (MD’s and PhD’s) regularly attend our seminars, which makes the event very unique. The topics are
generally broad in scope in order to accommodate the heterogeneous research minded community at our
Institution.
Finally, the Department of Pediatrics at USC/CHLA has committed institutional resources to Dr.
Vanderbilt’s development as a clinician-scientist. As a KL2 mentored career development award recipient, Dr.
Vanderbilt currently holds a 12-month position with 9 person-months (75% effort) protected for research
activities. This position and associated dedicated time for research would continue if he were to successfully
obtain K23 funding. He will continue to participate in USC/CHLA’s Early Faculty Development and Mentoring
Program, with an individual development and self-assessment plan to be reviewed with his primary mentor,
division chief, department chair, and other mentors/career advisors on a periodic basis. He will also have the
opportunity to receive feedback on academic presentations, manuscripts, and research through interactions
with faculty in the Divisions of General Pediatrics and Neonatology. The Department of Pediatrics will support
his travel to national meetings, as indicated in the Career Development Activities section, to support his
presentation of a first-authored paper. In addition to those resources, CHLA also regularly hosts
multidisciplinary research seminars and conferences that are directly relevant to areas of research interest
(see Facilities and Other Resources section). Please see signed Letter of Institutional Commitment from
Dr. D. Brent Polk, Chair of the Department of Pediatrics at USC/CHLA, for additional details on the institutional
commitment to Dr. Vanderbilt’s scholarship.

31

Facilities and Resources
Children’s Hospital Los Angeles (CHLA)
CHLA is located in the heart of metropolitan Los Angeles, has an established track record of high quality,
patient-oriented research and has been the recipient of numerous extramural awards, including funding from
NIH. CHLA is one of the largest children’s hospitals in the United States and proudly opened a new state-of-
the-art hospital in July 2011, increasing our capacity to 350 beds. It is a private, non-profit teaching hospital
affiliated with the Keck School of Medicine of the University of Southern California’s (USC) and is an active
partner in the USC Southern California Clinical and Translational Science Institute (SC CTSI), which is one of
the NIH CTSA centers. CHLA is ranked 8
th
in NIH funding for children’s hospitals and was named one of the
Nation’s top five best Children’s Hospitals U.S. News and World Report. The hospital treats more than 60,000
children annaully and admits more than 11,000 children inpatient every year, with more than 50% of them
under the age of five. Over 14,000 pediatric surgeries are performed annually, including heart and lung
transplants, cardiac catheterizations, neurosurgeries and orthopaedic procedures. The instituion is designated
as a Level I Pediatric Trauma Center and provides 35 pediatric critical care beds, more than any other hospital
in the Western United States.
CHLA is the largest pediatric facility in the western United States and is the principal pediatric center in the
Southern California. Founded in 1901, CHLA has been dedicated to serving the needs of critically and
chronically ill children with compassion, dedication, and excellence. As a community-based medical center
with an international impact, CHLA provides specialized, multi-disciplinary treatment and prevention services
for children and youth. Guided by a century of medical care, its mission is “to advance preventive services,
medical education and research in response to the needs of our community and in an atmosphere of love,
compassion and respect for people.” In 1932, CHLA and the University of Southern California signed an
affiliation agreement that made CHLA the principal pediatric teaching facility for the Keck School of Medicine.
Full time physicians (176) at CHLA have appointments in the Departments of Pediatrics, Surgery, Pathology,
Neurology, and Radiology at the Keck School of Medicine while the full time basic science faculty (36) holds
appointments in the Departments of Biochemistry, Cell Biology, Microbiology, and Physiology. CHLA is unique
because few pediatric hospitals in the world combine a freestanding clinical center with an on-campus
research facility – the CHLA Saban Research Institute. This link offers the ability within a single institution to
rapidly move discoveries from the research laboratories to the bedside of children suffering from complex and
life-threatening disease. Dedicated to advancing the limits of knowledge, the researchers at CHLA seek
solutions for childhood cancer, infections, genetic disease, developmental disabilities, and healthcare success.
The Saban Research Institute (TSRI) at CHLA
Established in 1992, TSRI is the umbrella under which research is conducted at CHLA. Its mission is to foster
an environment of scientific excellence where research will lead to discoveries involving the molecular and
clinical understanding of childhood development and implementation of procedures to diagnose, treat and
prevent pediatric diseases and promote child health. TSRI encompasses more than 90,000 square feet of
dedicated research space and it ranks fifth among 26 major pediatric research institutions across the country.
Researchers are involved in more than 200 active studies and projects, many of which are funded by NIH. The
Research Institute is affiliated with USC, and researchers are faculty members at the Keck School of Medicine
at USC. At any given time, more than 120 graduate students and post-doctoral fellows are in training.
Extramural funding for this research totaled $44,000,000 at the end of FY 2011, including $17,084,496 in NIH
funding. These research activities reflect a very significant expansion of TSRI over the past years. Extramural
funding has increased from $29 MM (total costs) in 2010 to $44 MM in 2011, and NIH funding was $19 MM in
2010 and $17 MM in 2011. Since the completion of the research facility, the Saban Research Building in June
of 2003, reflecting the strong commitment of CHLA to research, the Research Institute has been able to
actively recruit new research faculty members, increasing the pool of extramurally funded investigators over
100 in 2011.
The Clinical Investigation Center and the General Clinical Research Center support clinical research while
the Office of Research Advancement and Administration provides centralized support for all aspects of our
research. The Office of Advancement and Research Administration provides a centralized administrative
system that ensures that our research is maintained at the highest quality and safety levels. It includes pre-
and post-award administration, the Office of Technology Transfer, the Office of Operation and Facilities, and
satellite offices for Human Resources, Accounts Payable, Purchasing, and the Foundation. Extramural funding
for this research totaled $37,412,898.00 at the end of FY 2009, including $23,345,012.00 in NIH funding.
These research activities reflect a very significant expansion of Saban Research Institute over the past years.
In FY 2012, CHLA, received $16.6 million in NIH funding.
32

Southern California Clinical and Translational Science Institute
The Southern California Clinical and Translational Science Institute (SC CTSI) promotes translation of scientific
discoveries into new tools for clinical and community health. CHLA is an active academic partner with USC and
provides leadership and integration across components and services. Created by the US National Institutes of
Health (NIH), the SC CTSI is one of 60 research institutes nationwide that aim to speed research from
laboratories to sustainable public health solutions. Our focus: improving the health of diverse populations in
urban settings like Los Angeles. The SC CTSI is a partnership among leading Southern California academic,
clinical and community health organizations that jointly are working to identify major regional health problems –
and to direct world-class researchers and health care providers to develop new solutions for those problems.
The CTSI, and in particular its Center for Scientific Translation (CST), has developed an innovative service to
empower clinicians, engineers and scientists to pursue translational research. The service is designed for
multi-tiered translational engagement from discovery of targets to pre-clinical IND/IDE enabling translational
science. The CTSI has a Center for Education, Training, Career Development (CETCD) and a well-developed
Center for Biomedical Informatics Sciences (CBIS). The CETCD enhances our pipeline of physician-scientists,
offers formalized KL2 and T32 training programs, strongly addresses underrepresented minority research and
physician-scientist recruitment, and is led by a Co-mentor on the current proposal, USC Department of
Preventive Medicine Chair, Jonathan Samet, MD, MPH, who has extensive experience and expertise in issues
related to the training of clinicians in the conduct of research. The CBIS combines biomedical informatics and
biostatistical design under one umbrella to optimize service, training, data sharing and methodological
developments in relation to study design, information management, and data analysis. It provides services
and infrastructure that help to streamline publications, discovery, and query of data. CBIS provides data
transfer and management services, along with research support services such as bioinformatics, statistical
analysis, and the application and development of novel methods for translational research. The CBIS service-
oriented platform provides state-of-the-art Grid Security infrastructure that builds on a variety of security
standards to provide authentication and access control for the management and sharing of research
information and data. The Institute will offer opportunities for trainees for to become more familiar with the
conduit of translational research.

Computer:
CHLA research investigators have access to research computing facilities at the following sites: 1)
Workstations in their offices, 2) PC work stations in the Biostatistics lab located at CHLA. A computer lab is
designated for data entry, management and statistical support staff. E-mail and Internet access is provided to
all staff. In addition, the USC University Computing Services provides a comprehensive computing
environment to support instructional and research goals of the University and Its affiliated campuses including
CHLA. Facilities and services include campus-wide networking, a variety of central host systems, public user
rooms, and support for distributed systems, hardware maintenance, and user support services. It provides
support for and access to departmental and shared campus computing resources, library information systems,
and regional, national, and international information resources. USC utilizes the most up-to-date hardware
equipment and supports a variety of communication and scientific hardware and software systems. CHLA is
connected to USC’s health sciences network. Every research faculty and staff member has a computer on his
or her desk for database and statistical analysis, simulation, spreadsheet work, and text processing and has
the capability to communicate electronically.
The CHLA network operates on an NT based server supporting primarily Windows 7 and Windows XP
installations. In the current server environment, departmental servers are centralized into a fault-tolerant server
pool. The system is fiber-based and utilizes a T-3 connection to permit off site connections. The network
makes use of a Virtual Private Network (VPN) allowing a number of external connections and services
including gateways to the USC campus network and access to our internal electronic medical record system,
email, and personal files in a HIPAA-compliant manner. This network also provides both a vehicle to the
University Network of Libraries and other computer resources. CHLA uses a multitude of protocols in providing
network services in order to provide a mixed environment of both Windows and Non-Windows workstations.
The network is a full function network that provides access to and connection of many different applications
and services. All key personnel at CHLA have up-to-date computers with Internet connection and software for
spreadsheet work and text processing. Statistical software packages, including SPSS and Mplus, are
supported by partnerships with USC’s computing services. In addition, a project designated server will be
used to store the research data collected by the study, including qualitative and quantitative datasets,
transcripts, password protected files containing patient locator information, etc. The office automation suite is
33

comprised of Microsoft Office Professional Plus 2010, which includes Word, PowerPoint, Excel, Outlook, and
Access for all workstations, and CHLA also supports Visio, InfoPath, etc. as needed. Additional software and
hardware is available for the creation and modification of graphics, video editing, CD/DVD reproduction,
multimedia design, and statistical analysis. The Information Services (IS) department at CHLA provides
complete support for the workstation and network arena.
In addition to general CHLA/USC resources, the Division of General Pediatrics owns and operates a single
Polycom Unit for video conferencing. The equipment is located in the trainee meeting room, holding up to 50
people for training events or service clinics. The room is equipped with black-out blinds and a built-in LCD
projector. The Polycom Unit can toggle between the speaker and a computer-based, or monitor-run,
PowerPoint presentation. Division members also have access to video-teleconferencing equipment equipped
to bridge up to 5 sites at one time.

Office:
CHLA is located at 4650 Sunset Boulevard, in the Hollywood/Wilshire area of Los Angeles. The CHLA campus
includes a total of 198,000 net sq. ft. of research space, including the 10-story Smith Research Tower, the 5-
story Saban Research Building, an 8,000 sq. ft. Clinical Investigation Center, and a 10,000 sq. ft. Community
Health, Outcomes and Intervention Research Unit. The Principal Investigator has private office space within
the Division of General Pediatrics on the ground floor of the hospital. All faculty and research staff offices are
equipped with computers and broadband connections to the Internet, and there are numerous conference
rooms available to all hospital faculty and staff as well as a private conference room within the Division of
General Pediatrics. Additionally, the study team has access to resources at TSRI, which occupies five floors
holding 88,500-square-feet of bench laboratory space, several large conference rooms, the Neuroscience
Program and a 247 capacity auditorium.

Other:
The Children’s Hospital Health Sciences Library provides resources and services to CHLA staff. In addition to
its collection of 3500 print books and 170+ current print journal subscriptions, the library supplies access to
over 200 electronic books and 2000 electronic journals. Online access is available anywhere in the hospital or
from remote computers that connect to the USC network.
In addition to books and journals, the library also provides local and remote access to various journal article
databases including: Ovid MEDLINE, Ovid CINAHL, PubMed, PsycINFO, Science Citation Index, and Journal
Citation Reports. The library’s book and journal catalog, as well as that of the USC Norris Medical Library (with
whom the CHLA library has reciprocal borrowing agreements), is searchable online as well.
Library services include mediated literature searching (searches conducted by a librarian), interlibrary loan
borrowing (for obtaining materials that the CHLA library does not own), Ovid AutoAlerts (a current awareness
service that delivers weekly citations that match a researcher’s predefined topic), and HouseCalls (one-one-
one, time-of-need meetings where the librarian can instruct users on a variety of topics including database
searching, PowerPoint, or EndNote).

Abstract (if available)

Abstract Neonatal Intensive Care Unit (NICU) experiences are costly, associated with poor infant development, and highly stressful to the caregiver and the infant‐caregiver relationship—yet no comprehensive process model exists to describe the interplay of medical and environmental factors that determine development following a stay in the NICU. Support from this K23 mentored career development award will support the candidate to develop expertise in the multiple disciplines united by his research, with the ultimate goal of developing a theoretically informed preventive intervention to improve long‐term outcomes of vulnerable NICU survivors.

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Asset Metadata

Creator Vanderbilt, Douglas L. (author)

Core Title Relationships matter: contextualizing developmental outcomes of high risk infants

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical and Biomedical Investigations

Publication Date 10/24/2016

Defense Date 04/24/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag high risk infants,infant mental health,OAI-PMH Harvest,Relationships,traumatic stress

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Azen, Stanley P. (committee chair), Patino Sutton, Cecilia M. (committee member), Seri, Istvan (committee member)

Creator Email dvanderbilt@chla.usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-561396

Unique identifier UC11298999

Identifier etd-Vanderbilt-3400.pdf (filename),usctheses-c3-561396 (legacy record id)

Legacy Identifier etd-Vanderbilt-3400.pdf

Dmrecord 561396

Document Type Thesis

Format application/pdf (imt)

Rights Vanderbilt, Douglas L.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA