Improving the Detection of STIs in the Pediatric Emergency Department: A Pragmatic Trial
Phase: NA
Conditions: Gonorrhea, Chlamydia
Sponsor: Children's Hospital Medical Center, Cincinnati

Improving Detection of STIs in PEDs ED: A
Pragmatic Trial
(Adolescent STI)
PECARN Protocol Number 040
Pediatric Emergency Care Applied Research Network
National Institute for Child Health and Human Development
(NICHD)
Protocol Version 4.00
Version Date: December 17, 2019
Printing Date: December 17, 2019

Copyright c⃝2016-2019. University of Utah School of Medicine on behalf of the
Principal Investigators, Monika Goyal, MD, MSCE & and Jennifer Reed, MD, MS and
the Pediatric Emergency Care Applied Research Network (PECARN). All rights reserved.
This protocol is PECARN Protocol Number 040, and has been authored by Monika
Goyal, MD, MSCE & and Jennifer Reed, MD, MS, Children’s National Medical Center
& Cincinnati Children’s Hospital, for implementation with the PECARN investigators.
This study is supported by R01-HD071915 awarded to Children’s National Medical
Center & Cincinnati Children’s Hospital (PI:Monika Goyal, MD, MSCE & and Jennifer
Reed, MD, MS) by National Institute for Child Health and Human Development (NICHD).
The PECARN Research Node Centers are the University of Michigan at Ann Arbor,
Cincinnati Children’s Hospital Medical Center, Columbia University, University of Califor-
nia at Davis Medical Center, Children’s Hospital of Pittsburgh, and Children’s National
Medical Center are supported by Cooperative Agreements U03-MC00003, U03-MC22684,
U03-MC00007, U03-MC00001, U03MC22685, and U03-MC00006 from the Emergency
Medical Services for Children (EMSC) Program, Maternal and Child Health Bureau,
Health Resources and Services Administration.
This document was prepared by the PECARN Data Coordinating Center (DCC)
located at the University of Utah School of Medicine, Salt Lake City, Utah. The document
was written and typeset using LATEX2ε. The DCC at the University of Utah is supported
by Cooperative Agreement U03-MC00008 from the Emergency Medical Services for
Children (EMSC) Program, Maternal and Child Health Bureau, Health Resources and
Services Administration.

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PROTOCOL TITLE:
Improving Detection of STIs in PEDs ED: A Pragmatic Trial
Short Title: Adolescent STI
PECARN Protocol Number: 040
Lead Investigators and Authors:
Monika Goyal, MD, MSCE & and Jennifer Reed, MD, MS
Children’s National Medical Center & Cincinnati Children’s Hospital
Protocol Version: 4.00
Version Date: December 17, 2019
I conﬁrm that I have read this protocol, I understand it, and I will conduct the study
according to the protocol. I will also work consistently with the ethical principles that have
their origin in the Declaration of Helsinki and will adhere to the Ethical and Regulatory
Considerations as stated. I conﬁrm that if I or any of my staﬀare members of the Insti-
tutional Review Board, we will abstain from voting on this protocol, its future renewals,
and its future amendments.
Principal Investigator Name:
Principal Investigator Signature:
Date:
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Contents
1
Study Summary
8
1.1
Hypotheses
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.2
Speciﬁc Aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.3
Subject Eligibility, Accrual and Study Duration . . . . . . . . . . . . . .
8
2
Rationale and Background
9
2.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
2.2
Study Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
3
Overall Study Design
15
3.1
Study Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.2
Study Sample . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.3
Workﬂow Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.4
Pragmatic Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.5
Cost-eﬀectiveness analysis . . . . . . . . . . . . . . . . . . . . . . . . . .
17
4
Study Procedures
18
4.1
Screening and Enrollment
. . . . . . . . . . . . . . . . . . . . . . . . . .
19
4.2
Surveys
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5
Data Analysis
22
5.1
Speciﬁc Aim Analyses
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
5.2
Sample Size Calculations and Statistical Power . . . . . . . . . . . . . . .
23
6
Data Management
25
6.1
Clinical Site Data Management
. . . . . . . . . . . . . . . . . . . . . . .
25
6.2
Electronic Data Capture System . . . . . . . . . . . . . . . . . . . . . . .
25
6.3
Study Monitoring
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
6.3.1
Site Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . . . .
26
6.3.2
Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . .
26
6.4
Data Coordinating Center . . . . . . . . . . . . . . . . . . . . . . . . . .
27
6.4.1
Data Center Description . . . . . . . . . . . . . . . . . . . . . . .
27
6.4.2
Security and Conﬁdentiality . . . . . . . . . . . . . . . . . . . . .
28
6.5
Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
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7
Protection of Human Subjects
30
7.1
Institutional Review Board (IRB) Approval
. . . . . . . . . . . . . . . .
30
7.2
Waiver of Authorization
. . . . . . . . . . . . . . . . . . . . . . . . . . .
30
7.3
Waiver of Documentation of Informed Consent . . . . . . . . . . . . . . .
30
7.4
Waiver of Informed Consent for Chart Review . . . . . . . . . . . . . . .
31
7.5
Potential Risks
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.5.1
Improper Disclosure of Medical Information
. . . . . . . . . . . .
32
7.5.2
Medical Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.5.3
Social Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.6
Protections Against Potential Risks . . . . . . . . . . . . . . . . . . . . .
32
7.6.1
Improper Disclosure of Medical Information
. . . . . . . . . . . .
32
7.6.2
Social Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
7.7
Potential Beneﬁts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
8
Data and Safety Monitoring Plan
33
8.1
Data Safety Monitoring Board (DSMB) . . . . . . . . . . . . . . . . . . .
33
9
Study Training
33
9.1
Study Training
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
10 Regulatory Issues
34
10.1 Health Insurance Portability and Accountability Act
. . . . . . . . . . .
34
10.2 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . . . .
34
10.3 ClinicalTrials.gov Requirements . . . . . . . . . . . . . . . . . . . . . . .
34
10.4 Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
10.5 Public Use Data Set
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
List of Tables
1
STI Testing CDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
2
Power Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
List of Figures
1
Rates by State. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
2
Stepped Wedge Design.
. . . . . . . . . . . . . . . . . . . . . . . . . . .
17
3
Study Design.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
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Abstract
Sexually transmitted infections (STIs) are highly prevalent among adolescents.
Despite established principles for STI control, clinical practices related to screening
and diagnosis, treatment, and prevention of STIs among adolescents are subopti-
mal. There is an urgent need to expand our screening programs to nontraditional
healthcare settings such as emergency departments (ED) to reach those adolescents
who would otherwise not receive preventive healthcare, and to determine the most
eﬃcient and cost-eﬀective method for providing this screening. The goal of this
application is to leverage our recent insights obtained from single center ED-based
adolescent gonorrhea and chlamydia screening research and apply them across a
national pediatric ED research network to determine the most clinically eﬀective and
cost-eﬀective screening approach for adolescents when implemented into a real-world
clinical setting through a pragmatic trial. This will be accomplished through a net-
work of childrens hospital EDs with a track record of robust research collaboration
(Pediatric Emergency Care Applied Research Network or PECARN). This research
will contribute to the evidence base for creating clinically eﬀective, cost-eﬀective, and
sustainable Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT)screening
programs that can be successfully implemented into the clinical workﬂow of the ED.
It will also improve diagnosis of asymptomatic STIs and decrease the time interval
to treatment, consequently decreasing reinfection rates of transmission and the
overall STI burden as well as decreasing healthcare costs. This intervention will rely
on an innovative approach that electronically integrates patient-reported data to
guide clinical decision support. This work is signiﬁcant because it has the potential
to shift current ED clinical practice paradigms from only acute health encounters
to participation in the broader management of public health, and it will ﬁll gaps
in the literature needed to provide evidence for the best method of gonorrhea and
chlamydia screening in an ED setting. First, we will apply human factors modeling
methods to perform ED workﬂow evaluations at each participating pediatric ED to
determine the most eﬃcient way to integrate the screening process into everyday
clinical care. Following these analyses, we will conduct a comparative eﬀectiveness
pragmatic trial of targeted STI screening (screening only those disclosing high risk
sexual behavior) versus universally-oﬀered STI screening (oﬀered to all, regardless of
risk) through electronic integration of patient reported data for provision of clinical
decision support. We will then develop decision analytic models to evaluate the
cost-eﬀectiveness of targeted screening compared to universally oﬀered screening.
This research is novel in that it shifts the usual clinical practice paradigm in the ED
from STI diagnosis in symptomatic adolescents to STI screening and prevention, an
approach that is critical to addressing the STI epidemic among adolescents.
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1
Study Summary
1.1
Hypotheses
The hypotheses of this study are:
1a. A higher number of GC/CT infections will be detected during implementation of
universally- oﬀered and targeted screening strategies when compared to usual care.
1b. The eﬃciency (cases detected/patients tested) of GC/CT detection will be higher dur-
ing implementation of a targeted screening strategy when compared to a universally-
oﬀered screening strategy.
2a. Universally-oﬀered screening will NOT be cost-eﬀective compared with a targeted
GC/CT screening approach when applied to the overall population of adolescents
treated in emergency departments.
2b. Universally-oﬀered screening will be cost-eﬀective compared with targeted screening
in adolescent emergency department populations with a high prevalence of GC/CT.
1.2
Speciﬁc Aims
This project has the following Speciﬁc Aims:
Speciﬁc Aim 1. To compare the eﬀectiveness of usual care, targeted screening and
universally-oﬀered screening in EDs through a pragmatic trial that applies a human
factors systems approach to implement GC/CT screening into routine clinical care.
Speciﬁc Aim 2. To determine the most cost-eﬀective approach for GC/CT detection (i.e.
usual care, targeted screening, and universally-oﬀered screening) in an adolescent
ED population.
1.3
Subject Eligibility, Accrual and Study Duration
Eligible participants will be identiﬁed by on-site study staﬀ. Inclusion criteria are:
1. Males or females 15 up to and including 21 years of age.
Exclusion criteria are:
1. History of developmental delay; OR
2. Altered mental status; OR
3. Inability to provide consent for completion of the sexual health survey (SHS) and
STI screening; OR
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4. Critically ill; OR
5. Victims of sexual assult/abuse; OR
6. Unable to understand English.
2
Rationale and Background
2.1
Introduction
Adolescents are disproportionately aﬀected by sexually transmitted infections (STIs)1–3
and account for 9 million of the 19 million new STI cases annually.2 The STI epidemic
among youth is a national public health priority as noted in the Healthy People 2020 ob-
jectives, which speciﬁcally recommend enhanced STI diagnosis, treatment, and reduction
in adolescents.4 Failure to diagnose and treat STIs in a timely manner results in serious
reproductive morbidity, mortality, and increased transmission of disease.
Adolescents frequently access the emergency department (ED) for care,5–10 with the
ED functioning as the primary source of health care for over 1.5 million adolescents.9, 11, 12
EDs are potentially high-yield sites for the delivery of sexual health services as part of a
larger public health prevention strategy. Although the Centers for Disease Control and
Prevention recommend universal HIV screening in EDs,13 no recommendations currently
exist for gonorrhea and chlamydia (GC/CT) screening; thus <1% of the ED population
is screened for GC/CT.14 Addressing the eﬀectiveness and integration of ED-based STI
screening is critically needed.15, 16
Insuﬃcient knowledge of the ideal structure for delivery (i.e. universally-oﬀered or
targeted to high risk groups) is a barrier to the implementation of ED-based GC/CT
screening. While universally-oﬀered screening (oﬀered to all, regardless of risk) may detect
a larger number of cases than targeted screening (screening only those disclosing high
risk sexual behavior), it is more resource-intensive and may result in more false positive
cases due to a lower pretest probability of infection. The Co-PIs, Drs. Goyal and Reed,
are NICHD K23-funded investigators who are well-positioned to address this knowledge
gap. They each study targeted (Goyal) and universally-oﬀered (Reed) ED-based GC/CT
screening via electronically entered patient-reported data providing real-time clinical
decision support (CDS). They have shown that both strategies are acceptable, feasible,
and result in increased STI screening rates at their respective pediatric EDs;17–23 but it
is unknown which method is most eﬃcient and cost eﬀective when instituted across a
national sample of pediatric EDs with varying community STI prevalence.
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The scientiﬁc premise of this application is to leverage our recent insights obtained
from single center ED-based adolescent GC/CT screening research and apply them across
a national pediatric ED research network to determine the most clinically eﬀective and
cost-eﬀective screening approach for adolescents when implemented in a real-world clinical
setting through a pragmatic trial. To be successful and sustainable, the ideal screening
strategy must be easily incorporated into the clinical workﬂow. Electronic integration
of patient-reported data with CDS oﬀers one such solution with additional beneﬁts:
overcomes privacy concerns, circumvents provider biases about STI risk, and enables early
detection of infection before development of adverse sequelae. The objective of this study
is to compare targeted and universally-oﬀered STI screening approaches by seamlessly
integrating real-time CDS based on electronically-obtained patient-reported data into
the normal ED workﬂow through human factors analysis followed by cost-eﬀectiveness
analyses. We propose to execute a multicenter comparative eﬀectiveness pragmatic trial
within a national sample of pediatric EDs through the Pediatric Emergency Care Applied
Research Network (PECARN), a network of childrens hospital EDs with a track record of
robust research collaboration.
2.2
Study Rationale
The Burden of Adolescent STIs: Although adolescents and young adults represent
only 25% of the sexually active population, they comprise nearly 50% of all diagnosed
STIs annually. Of the 19 million new cases of STIs each year, over 9 million occur among
adolescents. Failure to diagnose and treat STIs in a timely manner can result in serious
reproductive morbidity and mortality, including pelvic inﬂammatory disease, ectopic
pregnancy, infertility, and facilitation of transmission of Human Immunodeﬁciency Virus
(HIV). Most importantly, failure to diagnose STIs leads to increased transmission of
disease, further increasing disease burden and contributing to the STI epidemic. The
STI epidemic among youth is a national public health priority identiﬁed in the Healthy
People 2020 objectives, which speciﬁcally targets enhanced STI diagnosis, treatment, and
reduction in adolescents.
Current Adolescent STI Screening Rates are Low: There is a general consen-
sus from the Centers for Disease Control and Prevention (CDC), American Academy
of Pediatrics, American College of Obstetrics and Gynecology, and the United States
Preventive Services Task Force (USPSTF) for at least annual Neisseria gonorrhoeae (GC)
and Chlamydia trachomatis (CT) screening in sexually active adolescents and young
adults. However, a national survey of youth noted only 11% reported being tested for an
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STI within the last 12 months. Many adolescents lack a medical home, placing them at
higher risk for non-detection of STIs. More than one-third of adolescents do not report a
source of primary care, and fewer than 15% of adolescents participate in yearly routine
health maintenance exams. However, even when adolescents do access primary care,
only 12% of sexually active females 15-24 years of age receive annual testing for GC/CT.
Among high school youth with a routine health maintenance exam within the prior 12
months, less than half report having discussed STI, HIV, or pregnancy prevention at
those visits. Despite STI screening being a HEDIS (Healthcare Eﬀectiveness Data and
Information Set) measure for health care quality and GC/CT screening considered to be
one of the most beneﬁcial and cost-eﬀective preventive services among young females, it
is also among the most underutilized.
The Emergency Department as a Strategic Venue for STI Detection and
Treatment: The USPSTF has deemed preventive health services to be eﬃcacious and
cost-eﬀective, and recommends that clinicians capitalize on all health visits, including
acute care visits, to provide preventive services. The ED may be a particularly strategic
venue for STI detection and treatment as adolescents comprise over 20 million ED visits
annually and more than 1.5 million adolescents receive their only medical care through
EDs. The CDC recommends annual GC/CT screening for all sexually active females <=
25 years of age and males who present to clinical settings with high prevalence of STIs.
Adolescents, and speciﬁcally minority and non-privately insured adolescents, are more
likely to access the ED than primary care oﬃces for STI care. Although many patients
do receive STI care in primary care settings, there has been a 17% decrease in adolescent
STI visits in these settings, and a 10% increase in adolescent ED visits in recent years.
Thus, the ED represents an additional setting for the provision of preventive services to
supplement care provided in primary care settings, with subsequent linkage back to the
medical home.
Current gaps in ED STI testing: Despite high rates of STIs in adolescents and
that the ED often functions as the only access to health care for many youth, STI testing
is not regularly conducted in the ED. Even when patients present with STI-related
symptoms, the performance of sexual histories and STI testing are underutilized, leading
to under-diagnosis and under-treatment. We previously reported that among adolescent
females presenting to the ED with potential STI-related complaints, almost 20% did not
have documented sexual histories or undergo STI testing. Sexually active and non-sexually
active adolescents are interested in learning about sexual health in the ED setting, and
a majority of adolescents presenting to the ED are accepting of STI testing, even when
presenting for non-reproductive health issues. Currently, there are no pediatric EDs that
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have implemented routine GC/CT screening into clinical practice. Rates of asymptomatic
GC/CT screening outside of the context of research studies include <1% of the population.
Therefore, if certain barriers to ED-based STI detection can be overcome, the ED may oﬀer
a strategic venue to address and improve the sexual health care of this high-risk population.
STI Screening vs STI Testing: There is often confusion as to what constitutes
STI testing versus STI screening. Testing typically involves patients who are symptomatic
or have a reason for testing, such as a recent known exposure. Alternatively, screening
involves an asymptomatic population of patients. Furthermore, STI screening may use
a universal approach where all adolescents are oﬀered screening, or a more targeted
approach, where only those with identiﬁed risk factors are screened.
Electronic surveys using patient reported outcome (PRO) measures may
help overcome ED STI screening barriers: There is growing interest in the use of
PROs in medicine as we strive to deliver patient-centered healthcare. PROs are deﬁned
by the FDA as any report of the status of a patients health condition, health behavior, or
experience that comes directly from the patient instead of through another individual
(e.g. healthcare provider, parent, etc.) and is not limited to health outcomes. Use of
PROs leads to better communication and decision-making between healthcare providers
and patients, and improves patient satisfaction and outcomes. The use of PROs to
ascertain information about sexual health among adolescents is particularly appealing
due to the sensitive nature of the topic. Adolescents cite privacy concerns as a potential
barrier to disclosing sensitive health information in the clinical setting. Obtaining sexual
health information conﬁdentially in the ED can be challenging due to space/privacy
issues, diﬃculty separating a patient from the caregiver in an acute setting, limited
time, competing priorities, and lack of clinical comfort and training. Electronic-based
surveys and interventions may obviate some of these barriers. Our previous qualitative
work demonstrates that adolescents and caregivers cite improved conﬁdentiality as one
of the beneﬁts of using tablet-based technology to oﬀer STI screening in the ED setting.
Electronic surveys not only provide a conﬁdential method for obtaining sensitive health
information, but they are also eﬃcient and patient friendly, as they can be tailored to an
individuals needs through the use of skip patterns and audio assistance. Adolescents do
not require a separate room for an interview, and thus, the surveys can be administered
while they are awaiting clinical care. This method is also provider friendly and allows for
an eﬃcient way to ascertain sensitive health information.
Clinical Decision Support (CDS) can improve patient and process-oriented
outcomes: CDS can be used to aid clinicians and patients in making healthcare decisions.
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CDS facilitates shared decision-making using patient-speciﬁc data and clinician decision
aids. In a systematic review of over 70 randomized controlled trials of CDS, improvement
in clinical practice was seen in 68% of the included studies. When applied eﬀectively,
CDS increases quality of care, enhances health outcomes, helps avoid errors and adverse
events, improves eﬃciency, reduces costs, and boosts provider and patient satisfaction.
Targeted vs.
Universally Oﬀered STI Screening for the ED setting: Al-
though the CDC recommend universal HIV screening in EDs, there are currently no
recommendations for GC/CT screening. Both existing research and expert consensus
support the need for research addressing the eﬀectiveness, sustainability, and integration of
ED-based STI screening programs. Determining the best screening strategy (universally-
oﬀered or targeted testing of patients at risk for STIs) for the ED setting requires further
investigation. Universally oﬀered screening provides many beneﬁts: it removes patient
stigma, circumvents provider biases about STI risk, eliminates questions regarding sexual
activity, results in early detection of infection prior to the development of adverse sequelae,
reduces the public health burden of STIs, and provides opportunities for risk-reduction
counseling. Universally oﬀered STI screening also eliminates many of the barriers to
current STI detection in an ED setting, including practitioners who may lack the time
to address sexual health among patients presenting with non-STI related complaints.
However, due to the additional costs of testing a larger number of individuals at low risk,
universally oﬀered screening may not be cost-eﬀective compared with a targeted approach.
A universally-oﬀered screening approach may also result in a higher false positive rate due
to a lower pretest probability of infection. This can result in greater downstream costs
associated with conﬁrmatory testing, exposure to unnecessary antibiotics, and potentially
avoidable emotional distress. Therefore, targeted screening may share many of the beneﬁts
of universally oﬀered screening with respect to increased asymptomatic detection, removal
of patient stigma, opportunities for risk-reduction counseling, and eﬃciency, but overcome
some of the potential disadvantages. Regardless, in order to be successful and sustainable,
the ideal screening strategy must be easily incorporated into the clinical workﬂow of busy
EDs. Electronic integration of PROs in combination with healthcare provider CDS oﬀers
one such solution.
Integrating PROs with the EHR for CDS: We propose to engage in health
process redesign and use electronic surveys with EHR integration and CDS to eﬃciently
and eﬀectively improve clinical care in the ED and evaluate the most eﬀective approach
to GC/CT screening. Practice-based research is a necessary step before implementation
of a new strategy into practice. Thus it is important to integrate the traditional forms of
research with health system redesign methods to translate discoveries from laboratory
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to patient and ultimately to the health care delivery system.24–26 Through the Co-PIs
individual K23 awards, Drs. Goyal and Reed have demonstrated that patient-reported
data can successfully be used to provide CDS to ED clinicians leading to an increase in
GC/CT testing rates.17, 22 Implemented independently, these two methods (PROs and
CDS) have proven successful in various ED and general pediatric clinical and process
improvement projects.27–31 To our knowledge, using health process redesign methods to
incorporate electronic PRO measurements into the EHR for the provision of real-time
CDS has not been used in implementing screening programs in an ED setting. CDS
features identiﬁed to be most important for improving clinical care include integration with
the electronic order entry system, request for documentation of reason for not following
system recommendations, and provision of the CDS at the time and location of decision
making.32 All of these features of CDS will be included in this proposal in addition to
conducting human factors workﬂow analyses at each participating ED for site-speciﬁc
adaptations. Integrating these CDS features will allow us to be optimally poised for
an accurate comparison of the diﬀerent GC/CT screening strategies. Furthermore, the
knowledge gained from workﬂow analyses at each participating site may help inform the
implementation of STI screening at other EDs and across other clinical settings. Our
long-term hypothesis is that using this novel system redesign to evaluate the eﬀectiveness
of universally-oﬀered versus targeted GC/CT screening interventions in the ED will lead
to an evidence-based approach that will ultimately decrease the overall rate of infected
adolescents. If this hypothesis is correct, large-scale ED-based GC/CT screening interven-
tions could be implemented to strengthen the potential impact of the ED health system
on population health. Using these methods will enable us to integrate an eﬀective GC/CT
screening method into the daily routine of an existing health care system. Furthermore,
if the aims of this research are successful, it has potential to serve as a model for other
ED-based screening interventions.
Scientiﬁc Premise: Although the ED can serve as a critical venue for the detection
and treatment of STIs, the optimal STI screening strategy (targeted vs universally-oﬀered)
has yet to be determined. Therefore, the scientiﬁc premise of this application is to leverage
our recent insights obtained from single center ED-based adolescent GC/CT screening
research and apply them, through a pragmatic trial, across a national pediatric ED
research network to determine the most clinically eﬀective and cost-eﬀective screening
approach for adolescents when implemented in a real-world clinical setting.
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Figure 1: Rates by State.
3
Overall Study Design
3.1
Study Setting
The study will be conducted at each of the 6 participating PECARN pediatric EDs,
which include Nationwide Childrens Hospital (Columbus, OH), Childrens Hospital of
Philadelphia (Philadelphia, PA), Lurie Childrens Hospital (Chicago, IL), Childrens
Hospital of Wisconsin (Milwaukee, WI), Denver Childrens Hospital (Denver, CO), and
Texas Childrens Hospital (Houston, TX). These sites provide geographic diversity while
allowing us to explore these STI screening approaches in high and low prevalence states
(see Figure 1)3 Each site has the Epic (Verona, WI) EHR and the IT resources to support
this study. All the sites will be monitored under PECARN and the Data Coordinating
Center (DCC) with individual site PIs and research coordinators (RC) designated at each
institution.
3.2
Study Sample
The study staﬀwill perform observations of adolescents seeking care in the ED who meet
eligibility criteria. Male and female patients 15 through 21 years of age will be included
regardless of their chief complaint, and only those patients who are unable to understand
English, who are critically ill, who are victims of sexual assault or abuse, have cognitive
impairment or altered mental status, or who would be unable to provide consent for
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completion of the SHS and STI screening will be excluded. The study population will be
limited to those patients available from the six sites during the speciﬁed collection time
periods.
3.3
Workﬂow Evaluations
The study research team will work with the sites to create ED workﬂow evaluations to
determine:
1. How best to integrate a new pathway in the EHR.
2. How best to integrate the new workﬂow of approach and consent in the Emergency
Department.
3. How best to integrate the use of the tablet in the workﬂow.
3.4
Pragmatic Trial
We will conduct a comparative eﬀectiveness pragmatic trial using a stepped wedge crossover
design.33 A stepped wedge design involves the sequential roll-out of an intervention or
a sequence of interventions to individuals or sites over multiple time periods. At the
end of the study, all sites will have received all interventions, but the order in which
sites are enrolled is randomly assigned. Once the ﬁnal intervention is implemented, that
intervention will continue until the end of the study. We considered many alternative
study designs and concluded that the stepped wedge crossover design is most appropriate
for this study as it will allow sites to act as their own controls, thus increasing eﬃciency
of the study, and allowing us to examine the eﬀect of time on the eﬀectiveness of an
intervention. This is important because in real-world clinical settings, adoption is not
100% and does not occur instantaneously. The design also allows us to control for the
eﬀects of secular trends (e.g. changes that are outside the interventions of the study). We
have designed this as a pragmatic trial because we want to evaluate the performance of
these screening strategies in routine clinical care, rather than under strict experimental
conditions.
Figure 2 presents an example step wedge design. Actual implementation may diﬀer,
but the general principals will be maintained. Sites will be randomized to one of these six
positions. Each time period, labeled 1 through 52, is a 2-week block of time. Using the
stepped wedge design, each site will ﬁrst begin baseline data collection (B) for a minimum
of 8 weeks. After collecting baseline data, each site will subsequently be randomized to
either start with implementation of a targeted screening intervention (T) or a universally
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Figure 2: Stepped Wedge Design.
oﬀered screening intervention (U). Each site will then cross-over and implement the
opposite strategy. The ﬁnal intervention will continue until the conclusion of the study.
We will include a 4-week washout (W) period between interventions during which we
will stop the intervention completely before starting the next intervention. Additionally,
the ﬁrst 2 weeks of each intervention will be considered a ramp-up period, and will be
excluded from data analysis.
3.5
Cost-eﬀectiveness analysis
Even if clinical strategies, such as universally oﬀered screening for STIs, are proven to
be eﬀective, the costs of those strategies compared with usual care or more targeted
approaches may make them impractical and unsustainable in a cost-constrained healthcare
system. Cost-eﬀectiveness analysis is a commonly used tool that allows policy makers and
clinicians to measure the beneﬁts gained for the additional costs of such strategies. The
result of a cost-eﬀectiveness analysis is the incremental cost-eﬀectiveness ratio (ICER),
which describes the additional cost of the more expensive but more eﬀective strategy being
examined, in this case universally oﬀered STI screening, compared with the lesser cost of
the less eﬀective strategy (we have hypothesized this will be targeted screening) divided
by the measure of eﬀectiveness being considered. The most commonly used metrics in
the peer-reviewed medical literature examine the incremental cost per quality-adjusted
life year (QALY) gained; however, any meaningful measure of eﬀectiveness can be used.
For this project, we plan to look at additional cost per STI detected, as well as cost per
QALY gained. We will develop decision analytic models (using Markov state transition
structure) to evaluate the cost-eﬀectiveness of universally oﬀered screening compared
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with targeted screening. To be complete, we also will include usual care as a third
strategy. A simple model will only examine eﬀectiveness in terms of STIs detected. A
more complicated model will include short- and long-term consequences of treated and
untreated disease. Short-term outcomes will include the likelihood of follow-up and
treatment once a diagnosis has been made, along with the eﬃcacy of antibiotic therapy.
Based on test characteristics from the literature, small numbers of patients may have false
positive or false negative test results. We will model the consequences of both, in terms
of additional costs and consequences of unnecessary treatment for false positives, and
the costs and consequences of undetected/untreated STI in the case of false negatives.
Outcomes also will be modeled for unscreened patients who later return for treatment
of symptomatic disease (e.g., acute pelvic inﬂammatory disease). Long-term outcomes
addressing the sequelae of untreated/ undetected STIs (tubal infertility, ectopic pregnancy,
and chronic pelvic pain) and outcomes following successful detection and treatment will
be modeled. Data generated from Aim 2 regarding the eﬀectiveness of the two screening
strategies in detecting GC/CT, the proportion of identiﬁed patients who ultimately
receive treatment, and the prevalence ranges of GC and CT in cohorts presenting for
ED care at the 6 sites in our study, will be used to inform probabilities in the model.
Literature-based estimates will inform other probabilistic events and costs of long-term STI
sequelae in the model. Incremental cost-eﬀectiveness ratios will be calculated to determine
cost-eﬀectiveness. The analysis will use a health care sector perspective34 that includes
medical costs borne by third-party payers and paid out-of-pocket by patients. These will
include current and future costs related to both the intervention and downstream events
related to treated or missed STIs. We will perform a series of deterministic sensitivity
analyses to explore the impact of parameter uncertainty on results, and known population
variations. A key parameter of interest is the background rate of STI. This likely varies
from location-to-location, and will be a key determinant to the cost-eﬀectiveness of the
universally oﬀered screening strategy. We will calculate the threshold of background STI
prevalence above which universally oﬀered screening becomes very cost-eﬀective (i.e.,
an ICER <$50,000/QALY). As a result, the cost-eﬀectiveness of the universally oﬀered
screening strategy may vary from location to location in the study, and in real-world use
of the screening tool. Understanding this threshold may help shape policy for optimal
screening strategies in diﬀerent locations and settings.
4
Study Procedures
Human Factors Workﬂow Analyses: Human factors workﬂow evaluations will oc-
cur at each of the 6 participating sites. A convenience sample will be obtained during
the times of CRC availability. These observations will be conducted to understand
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Figure 3: Study Design.
site-speciﬁc ED ﬂow diﬀerences that may occur with respect to the care of adolescents.
We will collect observational data regarding ED workﬂow and information exchange us-
ing the tool TaskTracker35 to record clinical workﬂow and identify common workﬂow paths.
Pragmatic Trial: Once the ideal workﬂow strategy is identiﬁed at each individual site,
all participants in both the targeted and universally oﬀered screening phases will use
a handheld tablet device to provide electronic informed consent for participation. All
participants will complete the previously developed and validated ACASI SHS containing
questions regarding their personal sexual health history.36 The PROs tool will risk-stratify
patients for STIs based on their reported sexual experience and/or presence of STI-
related symptoms. Using the tablet device, patients will also indicate their interest for
clinician-ordered STI testing (urine-based GC/CT). This will provide clinicians real-time
EHR-integrated decision support for GC/CT testing.
4.1
Screening and Enrollment
Since this is a pragmatic trial, the exact process of distributing tablets may diﬀer by
site and will be further clariﬁed during the workﬂow analyses. At some sites registration
staﬀmay be responsible for tablet distribution and at other sites triage or bedside nurses
may distribute the tablets. This will depend on the results of the workﬂow analysis. The
electronic informed consent document will contain information about the study. Should
questions arise, RCs will be available to answer more detailed questions. Research staﬀ
are available at each participating ED up to 16 hours per weekday and between 8-16
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Patient Classiﬁcation
CDS
At High Risk
STI Testing Highly Recommended
At Risk
STI Testing is Recommended
At Low Risk
STI Testing Not Necessary at this time
Table 1: STI Testing CDS
hours on weekends. During hours without RC presence, there will be a research-trained
clinical provider (with both protection of human subjects and good clinical practices
(GCP) training) present to answer questions. Reasons for not oﬀering the tablet will
be recorded by the ED staﬀ. Furthermore, if adolescents decline study participation, a
reason for refusal will also be recorded on the tablet.
• Targeted screening: During the targeted screening intervention, data from the
SHS will be integrated into the EHR and will provide CDS for GC/CT testing
based on SHS-calculated STI risk (developed and validated by Dr. Goyal). Patients
will be classiﬁed as at high risk for STIs if they disclose being sexually active and
have either the presence of STI-related symptoms or any of the following high risk
behaviors: more than 1 sexual partner in the last 3 months, no condom use during
last sex or prior history of STI. Patients will be classiﬁed as at risk if they disclose
being sexually active but do not disclose having any STI-related symptoms or any
high-risk sexual behaviors. Patients will be classiﬁed as at low risk if they deny
any history of sexual activity (see preliminary data for STI positivity rates by risk
strata). When patients classify as at high risk, clinicians will receive CDS that STI
testing is highly recommended; when they care for patients who classify as at risk,
they will receive CDS that STI testing is recommended; when caring for patients
who classify as at low risk, they will receive CDS that STI testing is not necessary
at this time. If the clinician chooses to follow the recommendation for screening
based on patients risk assessment, and the patient consents to testing on the tablet
device, urine GC/CT testing will be performed.
• Universally oﬀered screening: During the universally oﬀered screening interven-
tion, STI screening will be oﬀered to all eligible adolescents, regardless of risk. All
eligible patients will also complete the SHS, will be informed of the CDC GC/CT
testing recommendations and then be given the option to decline STI testing using
the tablet device. During this phase, the SHS results will not be available to the
clinician. STI testing recommendations will be based only on the patients decision
to undergo GC/CT testing. Like the process followed in the targeted screening
phase, if the clinician follows the CDS that informs the clinician that the patient
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agreed to GC/CT screening and consequently orders testing, urine GC/CT testing
will be performed.
• Both approaches: If the patient is at risk for STIs and declines GC/CT testing, or
the patient simply declines GC/CT testing on the tablet but the clinician believes the
patient should be tested, the clinician will have the opportunity to engage in a shared
decision-making process with the patient as per routine clinical care. Alternatively, if
the clinician declines the CDS GC/CT testing recommendations, he/she will be asked
to electronically document the reason the CDS is not being followed. All patients
who test positive for an STI will be notiﬁed of their results and provided treatment
based on each sites standard clinical processes for result notiﬁcation and treatment.
Among all patients tested for GC/CT, the associated primary care clinician (PCP)
will be informed of the testing and results via existing communication methodologies
including Epic in-basket messages, faxes, or other electronic communication methods,
and both patients and clinicians will be encouraged to schedule outpatient follow-up
appointments. Medical staﬀ, including faculty, clinical trainees, nurses and other
medical support staﬀ, will be educated about each screening intervention prior to
implementation and with frequent reminders, through in person staﬀmeetings,
emails, and Epic job aids.
4.2
Surveys
All data entered into the tablet by either the ED personnel or the patient will be stored
at the study site. This information will include the patients medical record number,
encounter ID, patients electronic consent to participate in the study, and survey responses.
For those patients who either do not meet inclusion criteria or refuse participation, exclu-
sion/refusal reasons will be documented by the staﬀand/or patients electronically and
stored in this database.
During implementation of the targeted screening intervention, the patient responses
to the SHS survey will categorize patients as at high risk, at risk, or at low risk for
STIs. This composite score will then be transmitted to the EHR through the Bridges
Interconnect system, a secure native interface allowing one-way transmission of data into
Epic. Bridges Interconnect is used to send data outside the Epic EHR into the EHR and
is available at all participating sites. CDS will be triggered on the EHR based on STI
risk strata as calculated by the SHS. During implementation of the universally oﬀered
screening, CDS for GC/CT screening will be determined by the patients decision to be
screened. If a patient agrees to GC/CT screening, that information will be transmitted
to the EHR through the Bridges Interconnect system, which will then trigger GC/CT
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screening CDS for the clinician.
5
Data Analysis
5.1
Speciﬁc Aim Analyses
Speciﬁc Aim 1. To compare the eﬀectiveness of usual care, targeted screening and
universally-oﬀered screening in EDs through a pragmatic trial that applies a human
factors systems approach to implement GC/CT screening into routine clinical care.
Human Factors Workﬂow Analyses: Data will be aggregated across observations and
workﬂow analysis will be performed to identify the most frequent tasks and interactions
during an ED visit. Transition diagrams will be created to examine overall workﬂow
processes which will include tasks performed, communication events between clinicians
and patients, and interactions with technology. Common patterns of activity will be
identiﬁed and used to inform deployment of the application to the patient and integration
with the EHR.
Pragmatic Trial: We will report descriptive statistics to summarize each primary
and secondary outcome variable. Our primary comparison of GC/CT screening strate-
gies will be targeted vs. universally oﬀered. We will compare detection rates (number
of STIs detected divided by the number of eligible, asymptomatic patients) using site
2-week period as the unit of analysis. Standard stepped-wedge analysis techniques will be
used. Speciﬁcally, the site detection rate over each 2-week period will be the outcome
in a linear model to examine the eﬀect of screening strategy on detection rate. In the
model, we will include a ﬁxed eﬀect for each site. To control for temporal trends, we will
model the eﬀect of time as a piecewise linear function with 8 three-month segments (i.e.,
cutpoints at the following times on the two-week scale: 0.5, 7, 13.5, 20, 26.5, 33, 39.5,
46, and 52.5 weeks). A three-level intervention eﬀect will be included, and we will test
for a diﬀerence between targeted and universally oﬀered screening at a 5% signiﬁcance
level. We will perform a similar analysis using the outcome of rate of positivity among
those tested for GC/CT. We will also calculate the proportion of visits during which
eligible patients agreed to GC/CT testing and compare them across the 2 STI screening
strategies (targeted vs. universally oﬀered). We will calculate the proportion of visits
during which clinicians follow the GC/CT testing CDS recommendations across the 2
GC/CT screening strategies and will perform multivariable logistic regression to identify
patient, clinician, and site-speciﬁc factors that may be associated with uptake of the CDS.
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As additional secondary outcomes, for patients who consent to SHS completion, we will
perform multivariable logistic regression to identify demographic and behavioral factors
associated with GC/CT testing consent and GC/CT positivity.
Speciﬁc Aim 2. To determine the most cost-eﬀective approach for GC/CT detection (i.e.
usual care, targeted screening, and universally-oﬀered screening) in an adolescent
ED population.
Cost-eﬀectiveness analysis: Markov state transition models will be built using readily
available software (Decision Maker, Boston, MA). Health states will include those that
impact prognosis, cost and quality of life, such as asymptomatic and symptomatic
infection with GC and/or CT, pelvic inﬂammatory disease, infertility, ectopic pregnancy,
and chronic pelvic pain. Because the median ED LOS for an adolescent is 4.25 hours,
and we have previously demonstrated no signiﬁcant diﬀerence in LOS between patients
who completed the SHS compared to those who did not,17 time to complete survey will
not be entered into the model. Furthermore, during a 4-hour ED visit, there is ample
time to collect a urine sample, and urine testing is often already requested for clinical
care. Therefore, time to obtain samples will also not be included in the cost analysis.
We will use a one-month cycle length and a life-long time horizon. Patients will move
between health states over time depending upon events that occur in each one-month
cycle of the simulation. Health states and events will have associated quality of life and
costs. We will perform analyses ﬁrst using base case estimates for all parameters. We
will next perform deterministic sensitivity analyses, examining key parameters one, two,
or three at a time, to explore the impact of uncertainty and to address other plausible
scenarios, such as populations with lower or higher prevalence of STIs. We also will be
able to test various cut points for the STI risk prediction tool, described in aim 2, to see
if there is an optimal cut point that minimizes the incremental cost-eﬀectiveness ratio,
ﬁnding the best balance between sensitivity and speciﬁcity for the risk prediction tool.
Finally, we will perform probabilistic sensitivity analyses, using second order Monte Carlo
modeling, to generate cost-eﬀectiveness acceptability curves, providing further insights
into the proportion of the time that the winning strategy will be cost-eﬀective.
5.2
Sample Size Calculations and Statistical Power
Workﬂow Analyses: We estimate that we will observe between 20-30 individuals per
site, which is a common sample size for studies of ED workﬂow processes.
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Diﬀerence
Power
0.5%
80%
0.75%
98%
1%
99%
Table 2: Power Calculations
Pragmatic Trial: We plan to enroll at 6 PECARN sites. Based on PECARN data,
with 6 sites for 52 two-week periods, we conservatively anticipate that approximately 288
patients or more per two weeks per site will arrive. Of these, we conservatively expect to
enroll 242 per site. About 220 of these will be asymptomatic and included in the primary
analysis. Our preliminary data reveal STI screening rates of 0.16% (usual care) leading
to detection rates less than 0.02%. Asymptomatic STI detection rates range from 4-10%
in a population of universally oﬀered screening. In a targeted population, which makes
up about 1/3 of the overall asymptomatic population, 10-14% will test positive. This
leads to estimated detection rates of approximately 3-5%. For power calculations, we
assume a detection rate of 4.5% using a targeted strategy and a standard deviation in
rates across sites of 2%. Based on expected enrollment of 220 asymptomatic patients per
time period per site, we will have approximately 99% power to detect a 1% diﬀerence
in detection rates, and over 80% power to detect a diﬀerence as small as 0.5% between
targeted and universally oﬀered strategies (see table above). A 1% diﬀerence in detection
corresponds to approximately 450 additional STIs detected per year at these sites alone.
If results from this study inform screening at centers across the country, the numbers
captured could be orders of magnitude higher. Additionally, we will also have adequate
power for subgroup analyses based on gender, age, race/ethnicity, and symptomatology,
as the design will provide over 90% power to show a diﬀerence in detection rates of 2%
for subgroups as small as 40 patients per month. Conﬁdence intervals around detection
rates in each of the screening strategy groups will be smaller than +/- 0.3%.
Cost-Eﬀectiveness Analysis: The sample size for the pragmatic trial will drive the
uncertainty around parameter value estimates for disease prevalence and the eﬀectiveness
of the two strategies in diagnosing STIs among patients with asymptomatic infection.
We expect to estimate detection rates within approximately 0.25%. The number of
cases detected and not detected in both strategies will be used to parameterize beta
distributions in the probabilistic sensitivity analyses.
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6
Data Management
6.1
Clinical Site Data Management
Each clinical site will maintain any research records in locked ﬁling cabinets and/or
password protected locations. The site will maintain an Essential Documents Binder,
which may be in paper or electronic form. Copies of all informed consent documents will
be kept on ﬁle and be available for site monitoring inspection (on site or remote).
6.2
Electronic Data Capture System
The Data Coordinating Center (DCC) will develop an electronic data capture system for
this trial. Currently the DCC uses multiple applications, such as OpenClinica or REDCap,
and will elect to use the most appropriate application at the time of implementation of
the study. Data will be entered by each clinical site.
The DCC will use an electronic discrepancy management system to notify sites of
inconsistent or erroneous data entry, which will be corrected by the clinical site. The
discrepancy management system maintains an audit trail of all discrepancy resolution.
All study information requiring EHR abstraction will be accessed through Epics
Clarity, a SQL-based querying tool available to all Epic sites. Data will include the
patients medical record number, encounter ID, demographics, STI orders, GC/CT results,
and information associated with the ﬁring of the CDS (i.e. user, actions taken, time ﬁred,
refusal reasons for the clinician not following the CDS), and follow up treatment data. In
addition to GC/CT test results, we will also abstract test results from any other STI test
that may have been ordered by the clinician, including testing for Trichomoniasis, Herpes
Simplex Virus, Syphilis, and HIV. These data will be merged with the tablet data using
the patient encounter ID for all adolescents who agree to participate.
Data will be abstracted daily during study implementation for quality checks and then
weekly via a CSV ﬁle. The data manager at each site will compile the data through this
automated process and results will be stored securely, accessible only by study staﬀ. The
data from the application database and EHR database will be automatically merged by
matching the patient encounter IDs as a unique identiﬁer. SQL code for this automated
merge was developed by Dr. Dexheimer at CCHMC and will be shared with each site.
The merged data at each site will then be stripped of patient names and a unique study
ID number will be attached to each encounter. This unique study ID will allow linkage of
the databases to allow for conﬁrmation of data in the event of data queries from the DCC.
The study team will develop a Manual of Operations for participating sites which will
include creation of data dictionaries, data transfer instructions, methods of encryption
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and conﬁdentiality requirements. Sites will export data monthly, and data cleaning and
quality assessment of each month’s data period will be completed prior to the data merge
and transfer to the DCC.
6.3
Study Monitoring
The investigators recognize the importance of ensuring data of excellent quality. Study
monitoring is critical to this process. Monitoring has been a very eﬀective tool for
maintaining data quality in previous Pediatric Emergency Care Applied Research Network
studies, and we will utilize this process to ensure excellent quality data in the proposed
study. Study monitors must be provided with appropriate access to study materials and
the medical records for study subjects. If the medical records are in electronic form, the
clinical investigator or an authorized individual must provide any assistance necessary to
facilitate the study monitor’s review of data in the electronic medical record.
6.3.1
Site Monitoring Plan
A supplemental study-speciﬁc risk-based monitoring plan, separate from the protocol
will be completed which outlines speciﬁc criteria for monitoring. This plan will include
the number of planned site visits, criteria for focused visits, or additional visits, a plan
for chart review and a follow up plan for non-compliant sites. The monitoring plan also
describes the type of monitoring that will take place (e.g., sample of all subjects within a
site; key data or all data), the schedule of visits, how they are reported and a time frame
to resolve any issues found. Remote site monitoring schedules will be determined by the
Data Coordinating Center in coordination with the study principal investigator.
6.3.2
Remote Monitoring
The Data Coordinating Center may supplement on-site monitoring with remote monitoring
activities. Remote monitoring involves detailed review of the data entered by the Clinical
Center and consultations with the Clinical Center investigator and/or research coordinator
to review safety and data quality. This may require uploading copies of speciﬁc parts of the
medical record, patient study ﬁle, regulatory documentation, or other source documents to
the Data Coordinating Center staﬀ, who review those materials against the data recorded
in the electronic data capture system. This helps assure protocol compliance and accurate
data collection. The Data Coordinating Center may conduct more remote monitoring
activities early in the trial to assure protocol compliance and identify any training issues
that may exist. Remote monitoring documents will be retained in accordance with federal
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requirements. Safety of subjects will be monitored and ensured in accordance with the
Data and Safety Monitoring Board (DSMB) plan.
6.4
Data Coordinating Center
6.4.1
Data Center Description
The Data Coordinating Center (DCC) in the Department of Pediatrics at the University
of Utah School of Medicine provides data coordination and management services for a
variety of national research networks. Anchoring these services is a new state-of-the-
art, energy eﬃcient data center completed in 2013. The data center facility supports
more than 1400 users around the world and provides a secure, reliable, enterprise-wide
infrastructure for delivering critical DCC systems and services. The new data center
was built using high industry standards and energy eﬃcient cooling solutions. The data
center is cooled by Rittal’s LCP inline cooling technology, providing eﬃciency, redundancy
and modularity. Cooling is based upon a hot/cold aisle design that allows for even air
distribution with minimal hot spots. The data center electrical power system contains a
redundant Mitsubishi uninterruptible power system (UPS) with a diesel backup generator.
The data center is protected with a FM200 ﬁre suppression system, early warning smoke
detectors and a heat detection warning system to act as a secondary system to the smoke
detectors. Security guards are on-site conducting access control and rounds 24/7/365.
Entry into the data center is restricted by card access and layered security measures and
controls. The data center and external building access points are monitored with video
surveillance.
In 2011 the data center began a large scale VMware server virtualization deployment.
Currently, the data center has virtualized about 99% of its environment. The virtual
environment consists of more than 200 virtual servers. The data center’s virtualization
solution provides key advantages:
• high availability – in the event of hardware failure, virtual servers automatically go
back online in a seamless process.
• ﬂexible infrastructure – disk storage, memory and processor capacity can be increased
or reallocated at any time.
• rapid deployment – servers can be provisioned on-demand with minimal waiting on
hardware of software.
The data center also enhanced its storage resources by implementing a networked
storage system to support its virtualized environment. The data center currently manages
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over 50 terabytes of data. The storage solution consists of Dell’s EqualLogic PS Series
Storage system for providing a virtualized storage area network (SAN). Some of the
beneﬁts that are realized through this technology are:
• storage architecture is no longer be a bottleneck for IT services;
• performance is better than with the previous architecture;
• tiered storage is now possible;
• provisioning and reclamation of SAN disk will be much easier; and most important,
• the new architecture includes a redesign of the SAN fabric to include complete
redundancy.
Production servers running critical applications are clustered and conﬁgured for failover
events. Servers are backed up with encryption through a dedicated backup server that
connects across an internal 10 gigabit network to a tape drive. DCC storage area net-
working (SAN) applications, clusters, and switch-to-switch links are also on a 10 gigabit
network. Incremental backups occur hourly Monday through Friday from 6 am to 6 pm.
Incremental backups also are performed each night with full system backups occurring
every Friday. Tapes are stored in a ﬁreproof safe inside the data center facility, and full
backups are taken oﬀsite on a weekly basis to an oﬀ-site commercial storage facility.
In the event of catastrophic failure, such as a ﬁre in the server facility, daily backups
would probably survive because of the ﬁre suppression system and ﬁreproof safe, but there
would be obvious delay in re-establishing data center function because the servers will not
survive such a disaster. Total destruction of the data center facility could cause the loss
of up to one week’s data. In future investments, the data center is making co-location,
disaster recovery and business continuity solutions a top priority.
DCC information systems are available 24 hours a day, 7 days a week to all users
unless a scheduled maintenance interruption is required. If this occurs, we notify all users
of the relevant systems, and data entry can be deferred until after the interruption is over.
Critical systems availability has exceeded 99.9% for the past two years, and there has
been no unscheduled downtime in over ﬁve years.
6.4.2
Security and Conﬁdentiality
The data center coordinates the network infrastructure and security with the Health
Sciences Campus (HSC) information systems at the University of Utah. This provides us
with eﬀective ﬁrewall hardware, automatic network intrusion detection, and the expertise
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of dedicated security experts working at the University. Network equipment includes four
high-speed switches. User authentication is centralized with two Windows 2012 domain
servers. Communication over public networks is encrypted with virtual point-to-point
sessions using transport layer security (TLS) or virtual private network (VPN) technolo-
gies, both of which provide at least 128 bit encryption. All of our Web-based systems use
the TLS protocol to transmit data securely over the Internet. Direct access to data cen-
ter machines is only available while physically located inside our oﬃces, or via a VPN client.
All network traﬃc is monitored for intrusion attempts, security scans are regularly run
against our servers, and our IT staﬀis notiﬁed of intrusion alerts. Security is maintained
with Windows 2012 user/group domain-level security. Users are required to change their
passwords every 90 days, and workstations time out after 5 minutes of inactivity. All ﬁles
are protected at group and user levels; database security is handled in a similar manner
with group-level access to databases, tables, and views in Microsoft SQL Server. Finally,
all laptop computers in use in the DCC or in the Department of Pediatrics are whole-disk
encrypted.
The data center uses control center tools to continuously monitor systems and failure
alerts. Environmental and network systems are also monitored to ensure up time. Highly
trained system administrators on staﬀare available to respond in high risk emergency
events.
All personnel involved with the DCC have signed conﬁdentiality agreements concerning
data encountered in the course of their daily work. All personnel (including administrative
staﬀ) have received Human Subjects Protection and Health Information Portability and
Accountability Act (HIPAA) education. We require all users to sign speciﬁc agreements
concerning security, conﬁdentiality, and use of our information systems, before access is
provided.
6.5
Record Access
The medical record and study ﬁles (including informed consent, permission, and assent
documents) must be made available to authorized representatives of the Data Coordinating
Center, upon request, for source veriﬁcation of study documentation. In addition, medical
information and data generated by this study must be available for inspection upon
request by representatives (when applicable) of the Food and Drug Administration (FDA),
NIH, other Federal funders or study sponsors, and the Institutional Review Board (IRB)
for each study site.
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7
Protection of Human Subjects
7.1
Institutional Review Board (IRB) Approval
The Data Coordinating Center and each clinical center must obtain approval from their
respective IRB prior to participating in the study. A central IRB (cIRB) at the University
of Utah will be used for this study. The Data Coordinating Center will track IRB
approval status at all participating centers and will not permit subject enrollment without
documentation of initial IRB approval and maintenance of that approval throughout
subsequent years of the project.
7.2
Waiver of Authorization
A waiver of authorization is requested in order to be able to pre-screen/establish eligibility
for subject prior to approaching, consenting, and enrolling a subject.
Human Factors Workﬂow Analyses: We are requesting a waiver of documentation of
written consent for Phase 1 as the workﬂow analyses are minimal risk and no identifying
information will be collected (no PHI). An information sheet will be provided to explain
why staﬀis outside the patient room and what information is being collected. Only
timings of and type of interaction with healthcare providers will be recorded by the
research staﬀ.
Pragmatic Trial: While adolescents <18 years will be encouraged to share study
participation with parents and/or guardians, a waiver of parental permission will be
requested as these participants are seeking conﬁdential health services. Minors in all
participating institutions are able to consent for testing and medical treatment related
to STIs without parental permission based on state laws. Under 45 CFR 46.408 (c),
an IRB has the authority to legally waive parental permission if it determines that a
research protocol is designed for conditions or a subject population for which parental
or guardian permission is not a reasonable requirement to protect the subjects, an
appropriate mechanism for protecting the children who will participate as research
subjects is substituted, and that the waiver is not inconsistent with Federal, State, or
local law.
7.3
Waiver of Documentation of Informed Consent
For the pragmatic trial, all adolescent patients meeting inclusion criteria who present to
the ED will be eligible for the study. Patients approached for survey completion via tablet
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will complete an electronic consent prior to survey administration. When handed the
tablet, the ﬁrst page will include a study information sheet. All participants, through the
electronic survey will provide electronic consent. We are requesting a waiver of written
documentation of informed consent/assent for these participants. This project meets the
requirements for a waiver of documentation as outlined in 45 CFR Part 46.117 in that
the only record linking the subject and the research would be the consent document,
and the principal risk would be potential harm resulting in a breach of conﬁdentiality.
This research presents no more than minimal risk to the subjects. Furthermore, state law
allows adolescents to consent for treatment related to sexual health. Therefore, a waiver
of parental consent will be requested in compliance with state law as well as to preserve
the conﬁdentiality of study participants. It is standard of care for health care providers to
interview adolescents privately, without the presence of a parent or guardian. Additionally,
it is standard of care for adolescents to be provided conﬁdential care for reproductive or
sexual health issues. Furthermore, obtaining written informed consent could place study
participants at even greater risk for breach of conﬁdentiality as a written document would
now associate the teen with participating in a study related to sexual health.
7.4
Waiver of Informed Consent for Chart Review
Waiver of consent is requested for observational data collection for each patient eligible
for this study. We are requesting data on all STI testing performed for all patients who
meet inclusion criteria as part of a chart review. This information will be abstracted in
aggregate form and no identifying information will be collected. This will be to measure
STI testing rates and STI prevalence among each site during each intervention.
The justiﬁcation for waiver of consent for the observational data collection in this
study is based on the following factors:
1. The scientiﬁc validity of the study is dependent on capturing all eligible patients
during the period of study, as one of the major goals is to accurately describe the
characteristics of the entire eligible population.
2. The study involves no intervention and collection of observational data will not
require any patient or parent contact.
3. The minimal risk of loss of privacy is mitigated by secure data management at the
DCC, and analysis datasets will be de-identiﬁed.
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7.5
Potential Risks
There is a minimal risk of loss of conﬁdentiality of the subject is a potential risk of the
study; however, safeguards are in place to protect against this.
7.5.1
Improper Disclosure of Medical Information
At each site, the investigators and study staﬀinvolved in the study will have access to PHI
about some or all subjects. All data will be submitted electronically using a secure system
hosted by the Data Coordinating Center. At the DCC, the DCC PI, data managers,
statisticians, and other staﬀmay have access to a limited set of identiﬁable information.
7.5.2
Medical Risks
There are no known or anticipated additional medical risks from participating in the trial.
7.5.3
Social Risks
Because sexual health and STIs can be a sensitive subject, some adolescents may feel
embarrassed discussing the topic and thus may refuse to participate in the STI screening
interventions. Unlike an adolescent clinic or other primary care setting in which parents
may be comfortable giving their adolescent privacy during his/her health care visit,
the ED setting is more challenging in this respect as many patients present with acute
issues accompanied by their parents. Furthermore, the ED is not always conducive
to conducting conﬁdential health interviews with patients due to ED design and space
limitations. However, state laws support conﬁdential STI screening for all adolescents, and
previous parent and adolescent qualitative data has shown that a tablet-based approach
is highly preferable when oﬀering STI screening. Therefore, computerized surveys can
help overcome the space-related challenges and conﬁdentiality related to sexual health
assessments in the ED. Based on our preliminary work, which has demonstrated high
rates of STI screening acceptance and interest among adolescents seeking care in the
ED18–2018 we do not anticipate this to be an issue.
7.6
Protections Against Potential Risks
7.6.1
Improper Disclosure of Medical Information
Loss of conﬁdentiality will be mitigated by the use of the Data Coordinating Center which
has a highly secure IT infrastructure, and by the existence of trained research staﬀat
participating sites. Data will be housed at the DCC where all ﬁles are protected and
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where all personnel at the DCC have undergone training and have signed conﬁdentiality
agreements. The investigators and staﬀof the DCC are fully committed to the security
and conﬁdentiality of data collected for the study. Violation of these agreements may result
in termination from employment at the University of Utah. In addition, all personnel
involved with the DCC data systems have received Human Subjects Protection and
HIPAA eduction. Each site will be responsible for ensuring that appropriate data security
procedures are in place.
7.6.2
Social Risks
Completion of the surveys is voluntary and subjects will be told that they do not have to
complete any questions that make them feel uncomfortable.
7.7
Potential Beneﬁts
The potential beneﬁt from participation in this study is that participation may lead to
the detection and treatment of undiagnosed STIs.
8
Data and Safety Monitoring Plan
8.1
Data Safety Monitoring Board (DSMB)
The study will have a Data Safety Monitoring Board (DSMB). The DSMB will have
a charter, will approve the protocol prior to implementation, and will review interim
analyses as applicable. The purpose of the DSMB is to advise the sponsors and Principal
Investigator(s) regarding the continuing safety of study subjects and the continuing
validity and scientiﬁc merit of the study. The DSMB is responsible for monitoring ac-
crual of study subjects, adherence to the study protocol, assessments of data quality,
performance of individual Clinical Center, review of serious adverse events and other
subject safety issues, and review of formal interim statistical analyses of treatment eﬃcacy.
9
Study Training
9.1
Study Training
A formal training program for investigators and research staﬀwill be held prior to
the start of enrollment. The training program will cover regulatory topics and Good
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Clinical Practice. The training will also provide in depth explanations regarding study
procedures, clinical care, data entry procedures, quality assurance, site monitoring, and
the informed consent process. A manual of operations will be provided to each investigator
prior to the start of enrollment. The manual will detail speciﬁc information about the
study procedures, regulatory information, protection of human research subjects, and
other necessary information. Updates and revisions to the manual will be made available
electronically. The Data Coordinating Center, in collaboration with the study investigators
will be the main contact for study questions.
10
Regulatory Issues
10.1
Health Insurance Portability and Accountability Act
Data elements collected include the date of birth and date of admission. Prior to statistical
analyses, dates will be used to calculate patient age at the time of the study events. The
ﬁnal data sets (used for study analyses and archived at the end of the study) will be
de–identiﬁed, and will exclude these speciﬁc dates.
Data elements for race, ethnicity, and gender are also being collected. These demo-
graphic data are required for Federal reporting purposes to delineate subject accrual by
race, ethnicity, and gender.
For purposes of the DCC handling potential protected health information (PHI) and
producing the de–identiﬁed research data sets that will be used for analyses, all study sites
have been oﬀered a Business Associate Agreement with the University of Utah. Copies of
executed Business Associate Agreements are maintained at the DCC.
10.2
Inclusion of Women and Minorities
There will be no exclusion of patients based on gender, race, or ethnicity.
10.3
ClinicalTrials.gov Requirements
This trial will be registered at ClinicalTrials.gov in accordance with Federal regulations.
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10.4
Retention of Records
For federally funded studies subject to the Common Rule, records relating to the research
conducted shall be retained for at least 3 years after completion of the research. Completion
of the research for this protocol should be anticipated to include planned primary and
secondary analyses, as well as subsequent derivative analyses. Completion of the research
also entails completion of all publications relating to the research. All records shall be
accessible for inspection and copying by authorized representatives of the regulatory
authorities at reasonable times and in a reasonable manner [45 CFR §46.115(b)].
10.5
Public Use Data Set
After subject enrollment and follow up have been completed, the DCC will prepare a
ﬁnal study database for analysis. A releasable database will be produced and completely
de-identiﬁed in accordance with the deﬁnitions provided in the Health insurance Portabil-
ity and Accountability Act (HIPAA). Namely, all identiﬁers speciﬁed in HIPAA will be
recoded in a manner that will make it impossible to deduce or impute the speciﬁc identity
of any patient. The database will not contain any institutional identiﬁers.
The DCC will also prepare a data dictionary that provides a concise deﬁnition of every
data element included in the database. If speciﬁc data elements have idiosyncrasies that
might aﬀect interpretation or analysis, this will be discussed in the dictionary document.
In accordance with policies determined by the investigators and funding sponsors, the
releasable database will be provided to users in electronic form.
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