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BMJ Open
Following young people with perinatal HIV infection from
adolescence into adulthood: the protocol for PHACS AMP Up,
a prospective cohort study
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Journal:
Manuscript ID
Article Type:
Date Submitted by the Author:
Complete List of Authors:
BMJ Open
bmjopen-2016-011396
Protocol
03-Feb-2016
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Tassiopoulos, Katherine; Harvard T.H. Chan School of Public Health,
Epidemiology
Patel, Kunjal; Harvard T.H. Chan School of Public Health, Epidemiology
Alperen, Julie; Harvard T.H. Chan School of Public Health, Epidemiology
Kacanek, Deborah; Harvard T.H. Chan School of Public Health, Biostatistics
Ellis, Angela; Frontier Science & Technology Research Foundation, Inc.
Berman, Claire; Harvard T.H. Chan School of Public Health, Epidemiology
Allison, Susannah; NIH, National Institute of Mental Health
Hazra, Rohan; NIH, Eunice Kennedy Schriver National Institute of Child
Health and Human Development
Barr, Emily; University of Colorado at Denver - Anschutz Medical Campus
Cantos, Krystal; Harvard T.H. Chan School of Public Health, Epidemiology
Siminski, Suzanne; Frontier Science & Technology Research Foundation,
Inc.
Massagli, Michael; Harvard T.H. Chan School of Public Health, Epidemiology
Bauermeister, Jose; University of Michigan School of Public Health, Health
Behavior and Health Education
Siddiqui, Danish; Tulane University Health Sciences Center, Pediatrics and
Infectious Diseases
Puga, Ana; Children's Diagnostic & Treatment Center
Van Dyke, Russell; Tulane University Health Sciences Center, Pediatrics
and Infectious Diseases
Seage III, George; Harvard T.H. Chan School of Public Health,
Epidemiology
Secondary Subject Heading:
Keywords:
HIV/AIDS
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<b>Primary Subject
Heading</b>:
Epidemiology
EPIDEMIOLOGY, PUBLIC HEALTH, World Wide Web technology <
BIOTECHNOLOGY & BIOINFORMATICS
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
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Title: Following young people with perinatal HIV infection from adolescence into adulthood: the
protocol for PHACS AMP Up, a prospective cohort study
Writing Team: Katherine Tassiopoulos DSc1, Kunjal Patel DSc1, Julie Alperen DrPH1, Deborah Kacanek ScD2,
Angela Ellis BS3, Claire Berman MS1, Susannah M. Allison PhD4, Rohan Hazra MD5, Emily Barr MSN6, Krystal
Cantos BA1, Suzanne Siminski MBA3, Michael Massagli PhD1, Jose Bauermeister PhD7, Danish Q. Siddiqui MPH8,
Ana Puga MD9, Russell Van Dyke MD8, George R. Seage III DSc1 for the Pediatric HIV/AIDS Cohort Study.
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, U.S.; 2Center
for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, U.S.;
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Frontier Science and Technology Research Foundation, Inc, Amherst, New York, U.S.; 4Division of AIDS
Research, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, U.S.; 5Maternal
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and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland, U.S.; 6Department of Pediatric Infectious Diseases,
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University of Colorado, Children’s Hospital Colorado, Aurora, Colorado, U.S.; 7University of Michigan, Ann
Arbor; 8Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, U.S.; 9Children’s
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Diagnostic & Treatment Center, Inc., Fort Lauderdale, Florida, U.S.
Corresponding author:
Senior Research Scientist, Department of Epidemiology
677 Huntington Ave., Kresge 817B
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Boston, MA 02115
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Harvard T.H. Chan School of Public Health
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Katherine Tassiopoulos, DSc, MPH
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Phone: 617-432-3265; Fax: 617-566-7805
[email protected]
Keywords: adolescents, transition to adult clinical care, internet, longitudinal studies, perinatal HIV infection.
Word count: 3356
Collaborator Statement: This article is being submitted for the Pediatric HIV/AIDS Cohort Study.
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ABSTRACT
Introduction: The first generation of adolescents born with HIV infection has reached young
adulthood due to advances in treatment. It is important to continue follow-up of these
individuals to assess their long-term medical, behavioral and mental health and ability to
successfully transition to adulthood while coping with a chronic, potentially stigmatizing
condition. To accomplish this, and to maintain their interest in long-term research participation,
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we need to accommodate the changing lifestyles and interests of young adult study participants
while ensuring valid data collection. We report the protocol for PHACS (Pediatric HIV/AIDS
Cohort Study) AMP Up, a prospective cohort study enrolling young adult participants for longterm follow-up.
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Methods and analysis: AMP Up is recruiting 850 young men and women 18 years of age and
older – 600 perinatally HIV-infected and a comparison group of 250 perinatally HIV-exposed,
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uninfected – at 14 clinical research sites in the United States and Puerto Rico. Recruitment began
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in April 2014 and is ongoing, with 305 participants currently enrolled. Planned follow-up is ≥ 6
years. Data is collected with a flexible hybrid of online and in-person methods. Outcomes
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include: transition to adult clinical care and retention in care; end-organ diseases; malignancies;
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metabolic complications; sexually transmitted infections; reproductive health; mental health and
neurocognitive functioning; adherence to antiretroviral treatment; sexual behavior and substance
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use; hearing and language impairments; and employment and educational achievement.
Ethics and dissemination: The study received ethical approval from the Harvard T.H. Chan
School of Public Health’s institutional review board (IRB) and from the IRBs of each clinical
research site. All participants provide written informed consent; for cognitively-impaired
individuals with legally authorized representatives, legal guardian permission and participant
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assent is obtained. Findings will be disseminated through peer-reviewed journals, conference
presentations and participant summaries.
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Strengths and limitations of this study
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The PHACS AMP Up study will enable long-term follow-up of perinatally HIV-infected
(PHIV+) young adults for evaluation of a wide range of clinical, behavioral and mental
health outcomes, as well as transition to adult clinical care and adult functioning;
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This study design allows flexibility in the transition from in-person to remote data
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collection, and can be adopted by other prospective epidemiologic studies concerned with
optimizing participant retention over the long-term;
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Since AMP Up is enrolling young adults through the PHACS research clinical sites,
participants may be more likely to be adherent to clinical care and supportive services;
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young adults non-adherent or lost to care may not be well-represented.
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INTRODUCTION
The first generation of youth perinatally-infected with HIV (PHIV+) has reached late
adolescence and young adulthood. The Pediatric HIV/AIDS Cohort Study (PHACS), the largest
long-term study of perinatal HIV infection in the US, has advanced understanding of the effects
of antiretroviral medications (ARVs) and HIV infection on infectious and non-infectious
complications, and metabolic, growth, cardiovascular, neurodevelopmental, neurological and
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behavioral outcomes among youth and adolescents.(1-17) Continued follow-up into young
adulthood is needed in order to assess the longer-term effects of HIV and ARVs on these
outcomes,(18, 19) and to examine issues specific to these emerging young adults, including the
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effects of transitioning from pediatric to adult health care on clinical and behavioral outcomes
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and retention in care, the attainment of milestones of adulthood including higher education and
employment, reproductive outcomes, and the risks of HIV transmission to sexual partners and
offspring.
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The PHACS Adolescent Master Protocol (AMP) is a prospective cohort study that
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enrolled youth with PHIV+ and a comparison cohort of perinatally HIV exposed, uninfected
youth (PHEU) who were 7-16 years old at enrollment. Participants are followed at 14 research
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clinic sites across the United States including Puerto Rico. The first AMP participants reached 18
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years of age in 2009. While overall study retention remains strong, we found that older AMP
participants were being disproportionately lost to follow-up. The AMP Up protocol was
therefore conceived as a protocol tailored specifically to young adults, in order to maximize
validity of data collection as well as retention of participants in continued long-term follow-up.
Development of novel strategies to optimize sustained research participation is a critical
challenge for all long-term epidemiologic studies,(20, 21) For young adults involved in
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longitudinal studies since childhood, participation may become less appealing as they gain
independence, secure employment or attend college and thereby become less willing or able to
return to clinics for study visits. An additional disincentive exists if the participant does not have
a personal connection with the study and its long-term objectives. Youth whose caregivers had
originally provided consent and managed study visit appointments must consent for their own
continuing follow-up once they reach the age of majority. This provides them with the
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opportunity to decline further participation in research. There are also special challenges inherent
with following youth with chronic conditions into young adulthood, including fatigue after years
of time-intensive clinical and research study visits, and the transition away from their pediatric or
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adolescent clinics, where their research visits often take place, into adult care clinics.(22)
Investigators conducting long-term research of young people with chronic, serious conditions
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such as HIV infection must consider the inevitable transition away from the strong support
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systems that often exist for these youth in pediatric care but which may not exist in adult care
systems,(23-25) and the resulting effect on participants’ willingness and ability to continue to
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participate in research as adults.
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The long-term success of epidemiologic studies of young adults will be built upon
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flexible study designs that are less time intensive and more accommodating of participants’
changing lifestyles than the clinic-based studies of their youth. A growing number of papers
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describe epidemiologic studies that use computer- and cell phone-based data collection
strategies.(26-31) In this paper we describe the rationale for and development of AMP Up, a
prospective cohort study that uses a flexible hybrid of online and in-person data collection to
follow PHIV+ and PHEU youth as they enter adulthood. AMP Up was designed to address the
primary scientific objective of defining the impact of HIV infection and antiretroviral therapy on
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young people with perinatal HIV infection as they transition into adulthood.
METHODS AND ANALYSIS
Assessing feasibility of AMP Up protocol
While national surveys suggest that most young adults in the US access and frequently use the
internet,(32) socioeconomic disparities in access persist.(33) Many PHACS participants come
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from socioeconomically disadvantaged backgrounds,(2) and PHACS research site staff indicated
that some study participants might have limited internet access. To determine whether PHACS
participants would be able to complete the online surveys through which a large proportion of
data in AMP Up would be collected, we conducted a feasibility study to evaluate the use of
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internet and mobile devices and willingness to participate in online research by youth and young
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adults seen at PHACS research clinics. The results of this anonymous survey are summarized in
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Table 1. Most individuals accessed the internet more than once a day, and the majority reported
being willing to participate in online research.
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Table 1. Feasibility study results: responses from anonymous survey on internet and cell phone use by
participants at PHACS clinical research sites, 2012-2013 (N=300)
Characteristic
N (%)
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Age range
Female sex
African American race
16-27 years
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212 (70.7)
Hispanic ethnicity
70 (23.3)
PHACS participant
134 (44.7)
Internet frequency in past 3 months
>once a day
<once a day/>=once a week
<once a week/nevera
225 (75.7)
56 (18.9)
16 (5.4)
Type of internet at home
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DSL/cable
Dial up
Wireless/3G/4G
Don’t know
No internet at home
Missing
76 (25.3)
1 (0.3)
125 (41.8)
43 (14.3)
30 (10.0)
25 (8.3)
Type of cell phone
Smart phone
Phone that can send/receive texts
No phone/cell phone doesn’t text
240 (80.1)
26 (8.8)
34 (11.1)
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Cell phone with unlimited internet
Yes
No
Don’t know
Cell phone doesn’t access internet
No cell phone
207 (69.3)
52 (17.6)
6 (2.0)
6 (2.0)
28 (9.1)
Willingness to participate in online researchb
Talk on cell phone about health or other parts of life
Go online to answer questions about health or other parts of life
Go to lab instead of clinic for blood draw and other medical tests
199 (66.5)
230 (77.7)
190 (64.0)
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Except where indicated, missing responses to individual questions range from 0-4.
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2 respondents reported no use of internet in past 3 months.
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Proportion responding ‘definitely would’ or ‘probably would’.
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We also considered the cognitive ability of PHACS participants to complete internet-
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based instruments in AMP Up. The AMP protocol collects sexual behavior and substance use
information via an audio computer-assisted self-interview (ACASI), which is self-administered
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on a computer. If an ACASI is not completed at a given visit, the site records the reason. We
compared full scale IQ scores from the Wechsler Intelligence Scale for Children, Fourth Edition
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(34) for AMP youth unable to complete any ACASI due to cognitive limitations and those who
completed one or more ACASI. The results the ACASI review are summarized in Table 2. The
vast majority of AMP participants have completed at least one ACASI; the small number of
participants who have not completed an ACASI because of cognitive limitations have significant
impairments.
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Table 2. Feasibility study results: ACASI completion and cognitive status of PHACS AMP
participants
ACASI Completion Status
N (%)
Full Scale IQ Score,
mean (SD)a
P valueb
No ACASI completed due to cognitive
limitations
16 (2.6)
45.5 (8.4)c
<0.001
592 (97.4)
86.1 (15.3)c
≥ one ACASI completed
Abbreviations: ACASI, Audio computer-assisted self-interview.
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Full scale IQ score from Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV).
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From t-test.
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Due to missing WISC-IV, N for those without ACASI=12, N for ACASI completed =576.
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Based on the results of the internet use survey and the ACASI review, we expect that the
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vast majority of eligible AMP Up participants will be able to complete the online surveys
independently. However, as we describe below, we have incorporated accommodations for those
unable to do so.
AMP Up study design
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AMP Up is a prospective cohort study which conducts yearly online data collection for the
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majority of self-reported information, annual medical chart abstraction and STI specimen
collection, and three in-person clinic visits at Entry, Year 3, and Year 6. Individual participants
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will be followed for a minimum of 6 years. The study is currently recruiting, with 305
individuals enrolled thus far.
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Study population and inclusion criteria
The eligible study population for AMP Up includes all PHIV+ and PHEU young adults 18 years
of age and older previously followed in AMP (including those lost to follow-up in AMP), along
with other PHIV+ young adults with available lifetime history of ARV use, CD4 and HIV-1
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RNA, and major medical diagnoses. Perinatal HIV status must be documented in the patient’s
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medical chart. All eligible participants are recruited from one of 14 clinical research sites across
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the US including Puerto Rico. Enrollment opened in April 2014 to former AMP participants and
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in May 2015 to other PHIV+ individuals previously involved in non-PHACS research protocols
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at the clinical research sites. The targeted enrollment goal is 600 PHIV+ and 250 PHEU young
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adults.
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Evaluations and data collection methods
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The AMP Up protocol is measuring outcomes from a wide range of domains, including:
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transition to adult clinical care; employment and educational achievement; retention in health
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care; HIV end-organ disease outcomes (renal, hepatic, cardiac, pulmonary, and peripheral and
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central nervous system) and HIV-associated malignancies; metabolic complications
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(dyslipidemia, hypertension, insulin resistance, hyperlactatemia, excess adiposity and fat
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redistribution); sexually transmitted infections; reproductive health; mental health and
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neurocognitive functioning; adherence to antiretroviral treatment (ART); sexual behavior and
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substance use; and hearing and language impairments. The frequency of outcome and covariate
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measurement and data collection methods are summarized in Table 3, and then the specific
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information obtained with each method of data collection is described in detail.
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48 Table 3. Schedule of Evaluations for the PHACS AMP Up Study
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Study Visit
Data Collection
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Method
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Yr 1
Yr 2
Yr 3
Yr 4 Yr 5
Yr 6
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clinic)
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Demographic and Psychosocial Factors
Education, employment, housing
Online survey
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Health care utilization, transition to adult clinical
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Online survey
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Social support, friendships, self-efficacy
Online
evaluation
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Quality of life
Online survey
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Online
evaluation
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Physical activity
Nutrition
Medical and Neuropsychological Factors
Diagnoses1
Chart abstraction
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Online survey
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Medications
Chart abstraction
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Height, weight, blood pressure1
Chart abstraction
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Body measurements
Clinic visit
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Reproductive health
Online survey
Neurocognitive functioning
Online
evaluation
Mental health: depression screen
Interview
Mental health: psychiatric diagnoses
Interview
Hearing
Online
evaluation
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Language
Interview
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Labs done for clinical care
Chart abstraction
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Laboratory biomarkers2
Clinic visit
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Sexually transmitted infections
Self-collection
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Repository samples3
Clinic visit
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Behavioral Factors
Sexual behavior
Online survey
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Substance use
Online survey
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ART adherence
Online survey
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Pregnancies, fractures, hearing problems, height and weight are also self-reported in annual online surveys.
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Venous lactate/pyruvate, renal biomarkers, cardiac biomarkers, fasting lipids, glucose, insulin.
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Serum & plasma (EDTA & heparin), PBMC, throat wash/gargle, saliva, urine, vaginal swab.
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Data Collection Methods.
Medical chart abstraction.
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Medical and neuropsychological diagnoses, ARVs and other medications, reproductive history,
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laboratory measures, height, weight and blood pressure are abstracted from participants’ medical
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In-person clinic visits.
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Physical examinations, laboratory tests, interviewer-administered mental health evaluations
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(Client Diagnosis Questionnaire [CDQ];(35) Centers for Epidemiologic Studies Short
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Depression Scale [CES-D 10] (36)) and collection of repository storage specimens (blood, saliva,
urine, vaginal swabs) are conducted. Cognitive function, hearing, emotional health and
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friendship are assessed via the online NIH Toolbox(37) and language is assessed with the
interview-administered Clinical Evaluation of Language Fundamentals-4th edition (CELF).(38)
Physical activity is evaluated with the online Block Physical Activity Screener.(39)
Self-collection of sexually transmitted infection (STI) specimens.
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For participants without Neisseria gonorrhoeae and Chlamydia trachomatis testing results
available in medical records during the 12 months prior to a study visit, urine and vaginal swabs
are self-collected for STI testing at the local clinical laboratory. Additional urine and swab
samples are taken and sent to repository for further STI testing at a central research laboratory.
At in-person clinic visits, samples are self-collected at the clinic and at other time points are selfcollected either at the clinic or at home.
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Online survey.
The AMP Up online survey consists of a series of short modules with questions on the following
topics: employment/education/housing, health care, quality of life, sexual behaviors,
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reproductive health, substance use, nutrition, and for PHIV+ participants, adherence to ART and
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transition to adult clinical care. The survey also includes an acceptability question asking if
participants would prefer to take the survey at home, in the clinic, or elsewhere, and a test
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question to assess how closely participants read the survey instructions. The survey ends with
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optional questions to assess participants’ acceptability of the instrument.
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Input from members of the PHACS Young Adult Community Advisory Board (YACAB)
emphasized strong preference for short surveys that did not repeat questions that were answered
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in earlier surveys. We therefore developed surveys that can be completed at one or multiple
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sittings, and allow wide study visit windows. Skip patterns are embedded within and also
between surveys completed at different time points, allowing follow-up surveys to be tailored to
each participant based on their responses to previous surveys.
Participants can opt to complete surveys at their study clinic or offsite. For individuals
with cognitive limitations who cannot respond to survey questions on their own, we developed a
shorter online instrument consisting of a subset of the modules (employment/education/housing,
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health care utilization, medication adherence, and transition to adult HIV care) that can be
completed by their caregiver. Alternatively, participants who can respond on their own but
cannot self-administer the online instrument can complete a similar, interviewer-administered
online survey that also includes the quality of life module.
Upon completion of the survey, participants have the choice of a $75 virtual or physical
gift card. This remuneration is provided in addition to funds provided by the clinical site to
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compensate for food, travel, or participation in other study activities.
The online surveys were piloted by research and clinic staff, YACAB members, and
other young adult volunteers from outside of PHACS. Surveys are thoroughly tested prior to
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implementation to ensure the proper placement and function of skip patterns. Responses to the
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surveys are regularly reviewed to allow for modification of potentially unclear questions.
Training and implementation
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Given the novelty of internet-based instruments and remote data collection to PHACS staff and
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participants, we created written instructions to guide them through important study processes,
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including study registration, specimen sample collection for STI testing, registration and
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navigation of the NIH Toolbox, and organization of the Entry visit. The importance of the inperson Entry visit is emphasized in the instructions, as it provides initial administration of the
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online survey in a familiar setting, and preparation for the Year 1 follow-up visit where the first
instance of remote data collection may take place.
Research sites’ role in data collection and participant engagement
Given that staff at the pediatric/adolescent clinics are often an important part of participants’
systems of support, research site staff have emphasized that their relationship with participants
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should be maintained during this potentially turbulent period. The AMP Up protocol was
therefore designed with flexibility in terms of the research sites’ role in data collection and
participant engagement, allowing participants to determine a comfortable pace by which to
transition from clinic-based research visits to remote online data collection. Initially, AMP Up
site staff will be integrally involved with all participants through study enrollment and
completion of Entry visits. For a certain subgroup of participants, this level of site involvement
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will continue throughout the duration of the protocol due to personal preference or because of
lack of internet access or cognitive limitations. However, it is anticipated that the ability and
willingness of most young adults to return to the clinic will diminish and eventually end due to
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competing priorities; therefore accommodations have been incorporated to allow for their
continued study participation entirely off-site, through chart abstraction, online data collection,
and mailed-in specimen collection.
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Sample size
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Our targeted sample size of 600 PHIV+ and 250 PHEU young adults will allow us to address
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AMP Up’s primary scientific objective of defining the impact of HIV infection and antiretroviral
therapy on young adults with perinatal HIV infection as they transition into adulthood. In the
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context of this study, we will be measuring many targeted outcomes, some continuous (e.g.,
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neurocognitive functioning defined as full scale IQ score) and some binary (insulin resistance,
retention in adult clinical care). For comparisons between PHIV+ and PHEU young adults,
continuous outcomes, the target sample size of 600 perinatally-infected versus 250 uninfected
participants for the AMP Up study provides 80% power to detect a difference in means for a
continuous outcome of 0.211 standard deviations based on a 2-sample t-test (assuming normality
holds), and 0.216 based on a non-parametric Wilcoxon rank sum test (for skewed outcomes) at
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alpha = 0.05. For example, if we were comparing the full-scale IQ scores of HIV infected vs.
uninfected participants and assumed a standard deviation of 15 points, we could detect a
difference of 3.16 points or more in the mean IQs. If we allow for possible loss to follow-up or
incomplete/missing assessments of 4% per year for infected and 6% per year for uninfected
participants for three years after enrollment into AMP Up is completed, then an adjusted sample
size of 530 HIV-infected vs. 208 HIV-uninfected participants provides 80% power to detect a
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difference of 0.229 standard deviations, or 3.44 points in mean IQ scores. Once we adjust for
potential confounders, we will typically lose some power so the minimum detectable difference
will usually increase.
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For binary outcomes, the minimum detectable odds ratios we can detect based on
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comparing HIV-infected vs. uninfected participants, at 80% power with a 0.05 significance level,
ranges from 1.57 to 2.64 depending on underlying rate of the event in the comparison (PHEU)
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cohort, which we have varied in these sample size calculations to be between 4% and 30%. For
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simplicity here, it is assumed that the event rate is higher in the HIV-infected group than the
PHEU group.
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For comparisons within PHIV+ young adults we may wish, for example, to compare
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those PHIV+ young adults who initiated ART before age 5 versus those who initiated ART at a
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later age. The detectable differences in means relative to the standard deviation that can be
detected assuming 530 PHIV+ participants (under an assumption of 4% loss per year) when two
subgroups of the PHIV+ participants are being compared ranges from 0.24 to 0.41, depending on
the sample percentages in each subgroup. When comparing proportions with events between
two subgroups, the minimum detectable odds ratios range from 1.63 to 4.01 depending on the
percent in each subgroup.
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Statistical analyses
Participants’ baseline characteristics (including demographics and clinical characteristics) will be
described using frequencies for categorical variables and means, medians, standard deviations
and interquartile range for continuous variables. Incidence estimates for outcomes will be
calculated under a Poisson distribution based on participant-years of follow-up.
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When evaluating associations between the many exposures and outcomes of interest in
this study, multivariable regression analyses will be conducted adjusting for potential
confounding factors. For cross-sectional associations, logistic and linear regression models will
be used. Cox proportional hazards models will be used for factors associated with incidence of
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commonly-occurring outcomes, and Poisson regression for incidence of outcomes that are
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observed to occur less frequently. For evaluation of factors associated with changes in outcomes
over time, generalized estimating equation (GEE) or mixed effects models will be employed.
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Effect modification of associations by specific covariates will be evaluated by adding interaction
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terms to the multivariable regression models. A probability level of 0.05 will be used for all
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analyses.
All analyses will be conducted using SAS Version 9.2 (SAS Institute Inc., Cary, NC).
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ETHICS AND DISSEMINATION
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The AMP Up protocol was approved by the Harvard T.H. Chan School of Public Health’s
Institutional Review Board (IRB) as well as the IRBs at the 14 participating sites. Participants
provide written informed consent; for cognitively-impaired individuals with legally authorized
representatives, legal guardian permission and participant assent is obtained.
To protect participant confidentiality, in addition to an anonymized Participant Identifier
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assigned to all PHACS participants, AMP Up participants are assigned a Personal Identification
Number and Keyword to enter and submit online survey data. Written instructions were also
developed for participants to provide steps to maintain their privacy when participating in webbased research. DatStat,(40) which hosts the AMP Up online surveys, maintains stringent levels
of encryption and data storage that exceed both industry standards for Internet security and IRB
standards for the protection of research participants and electronic records. DatStat’s technology
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platform, including servers, databases, and web presences, employ multiple layers of security
features to protect research participants and their data.
Dissemination
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The findings from this study will be disseminated through peer-reviewed journals, national and
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international conference presentations, and to study participants through participant summaries
that are presented in YACAB newsletters and in a recently-developed participant website.
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DISCUSSION
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Many PHACS participants have a strong connection with their clinical research site, as expressed
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by YACAB members and site staff. This connection may minimize the participation and
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retention issues experienced by other epidemiologic studies recruiting and following participants
entirely online.(41) The long-term success of AMP Up will be tested as more participants
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relocate, attend college, transfer their clinical care to adult clinics (a process typically completed
by age 25), or take on work and family responsibilities that preclude them from completing study
assessments in the clinic at which they enrolled in AMP Up. While our initial success may hinge
upon the strong connections participants have with their sites, in order to successfully transition
them to remote visits we will need to encourage direct connections between participants and the
PHACS study itself. For this reason we are taking steps to strengthen the association AMP Up
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participants have with PHACS. This began with the involvement of AMP participants in the
development of AMP Up, and has continued with the development of the YACAB and of the
participant website, through which participants link to their online surveys, access information
on health, education and housing opportunities, and connect with other study members.
Given it will be important for the majority of AMP participants to successfully enroll into
AMP Up as they reach 18 years of age, we are beginning to examine enrollment trends and
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reasons for not enrolling. Additional challenges in recruitment and study retention will arise
when AMP Up opens enrollment to PHIV+ young adults not previously involved in research
protocols at our research clinics. We are exploring methods to offer web-based informed
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consent forms, enrollment and medical record release authorizations for these potential
participants.
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In some aspects the first generation of perinatally HIV-infected youth is unique. Many of
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these young people were born before the advent of effective antiretroviral therapy and were not
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expected to live past childhood. This expectation may have profound consequences for their
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transition into young adulthood, a transition which is of particular research interest both
domestically and internationally. To potentiate the opportunity to collaboratively study
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transition, we have shared the AMP Up protocol and online survey instrument with other, global
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networks whose aims include an examination of the transition into adult clinical care for young
people infected with HIV, including the International Epidemiologic Databases to Evaluate
AIDS (IeDEA) (42) and EuroCoord.(43) The design of AMP Up, which allows flexibility in the
transition from in-person to remote data collection, can also enhance long-term research
possibilities for a broader set of studies. Investigations undertaking long-term follow-up of
young adults with chronic conditions, including birth or early childhood cohorts, or more
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generally, any epidemiologic studies for which long-term success is contingent upon the ability
to retain participants’ interest and long-term commitment, can potentially benefit from adopting
this study design.
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Author contributions: Author KT was integrally involved in conception and design of the
protocol and drafting of the manuscript; authors GS, RVD, RH and SA were integrally involved
in conception and design of the protocol, reviewed the manuscript and provided revisions; author
KP was involved in design of the protocol and provided critical input on content and
organization of the paper; author JA was involved in design and implementation of the protocol,
wrote segments of the manuscript’s Methods section and provided critical feedback on the
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manuscript in full; authors KC, SS, MM, AE, CB and DK were involved in development of one
or more of the protocol’s data collection instruments, reviewed the manuscript and provided
important revisions; authors JB and DS provided important insight as to the structure and content
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of the online survey instrument, reviewed and revised the manuscript, and authors EB and AP
participate in data acquisition and reviewed and revised the manuscript.
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Competing Interests: No, there are no competing interests
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Funding: The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice
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Kennedy Shriver National Institute of Child Health and Human Development with co-funding
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from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious
Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National
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Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other
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Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of
Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism,
through cooperative agreements with the Harvard T.H. Chan School of Public Health
(HD052102) and the Tulane University School of Medicine (HD052104).
Note: The conclusions and opinions expressed in this article are those of the authors and do not
necessarily reflect those of the National Institutes of Health or U.S. Department of Health and
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Human Services.
Acknowledgements:
We thank the children and families for their participation in PHACS, and the individuals and
institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy
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Shriver National Institute of Child Health and Human Development with co-funding from the
National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the
Office of AIDS Research, the National Institute of Mental Health, the National Institute of
Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication
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Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and
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Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through
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cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102)
(Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University
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School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal
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Investigators: Kenneth Rich, Ellen Chadwick; Project Director: Patrick Davis). Data
management services were provided by Frontier Science and Technology Research Foundation
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(PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat,
Inc (PI: Julie Davidson).
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The following institutions, clinical site investigators and staff participated in conducting PHACS
AMP and AMP Up in 2015, in alphabetical order: Ann & Robert H. Lurie Children’s
Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter;
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Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris;
Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron;
Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Patricia Garvie,
James Blood; Children’s Hospital, Boston: Sandra Burchett, Nancy Karthas, Betsy Kammerer;
Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; Rutgers - New Jersey
Medical School: Arry Dieudonne, Linda Bettica, Susan Adubato; St. Christopher’s Hospital
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for Children: Janet Chen, Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant; St. Jude
Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan
Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera;
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Tulane University Health Sciences Center: Margarita Silio, Medea Jones, Patricia Sirois;
University of California, San Diego: Stephen Spector, Kim Norris, Sharon Nichols;
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University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Alisa Katai,
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Jennifer Dunn, Suzanne Paul; University of Miami: Gwendolyn Scott, Patricia Bryan, Elizabeth
Willen.
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Conflicts of Interests: None reported.
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and methods. Epidemiology 2002;13(6):640-5.
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Smith B, Smith TC, Gray GC, et al. When epidemiology meets the Internet: Web-based surveys
in the Millennium Cohort Study. Am J Epidemiol 2007;166(11):1345-54.
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Weisel CP, Weiss SH, Tasslimi A, et al. Development of a Web-based questionnaire to collect
exposure and symptom data in children and adolescents with asthma. Ann Allergy Asthma
Immunol 2008;100(2):112-9.
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Huntington A, Gilmour J, Schluter P, et al. The Internet as a research site: establishment of a
web-based longitudinal study of the nursing and midwifery workforce in three countries. J Adv
Nurs 2009;65(6):1309-17.
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Huybrechts KF, Mikkelsen EM, Christensen T, et al. A successful implementation of eepidemiology: the Danish pregnancy planning study 'Snart-Gravid'. Eur J Epidemiol
2010;25(5):297-304.
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van Gelder MM, Bretveld RW, Roeleveld N. Web-based questionnaires: the future in
epidemiology? Am J Epidemiol 2010;172(11):1292-8.
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Lenhart A. Teen, Social Media and Technology Oveview 2015. 2015.
(http://www.pewinternet.org/files/2015/04/PI_TeensandTech_Update2015_0409151.pd).
(Accessed January 2016).
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File T, Camille R. Computer and Internet Use in the United States: 2013. American Community
Survey Reports, ACS-28. Washington D.C.; 2014.
(https://www.census.gov/content/dam/Census/library/publications/2014/acs/acs-28.pdf).
(Accessed December 2015).
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Wechsler D. The Wechsler Intelligence Scale for Children-Fourth Edition. San Antonio, TX: The
Psychological Corporation; 2003.
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Aidala A, Havens J, Mellins CA, et al. Development and validation of the Client Diagnostic
Questionnaire (CDQ): A mental health screening tool for use in HIV/AIDS service settings.
Psychol Health Med 2004;9:362-80.
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Zhang W, O'Brien N, Forrest JI, et al. Validating a shortened depression scale (10 item CES-D)
among HIV-positive people in British Columbia, Canada. PLoS One 2012;7(7):e40793.
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Gershon RC, Wagster MV, Hendrie HC, et al. NIH toolbox for assessment of neurological and
behavioral function. Neurology 2013;80(11 Suppl 3):S2-6.
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Semel E, Wiig E, Secord W. Clinical evaluation of language fundamentals-4th edition. San
Antonio, TX: The Psychological Corporation 2003.
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NutritionQuest. Block Physical Activity Screener - Adults.
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DatStat. DatStat. (http://www.datstat.com). (Accessed January 2016).
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Bajardi P, Paolotti D, Vespignani A, et al. Association between recruitment methods and attrition
in Internet-based studies. PLoS One 2014;9(12):e114925.
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International Epidemiologic Databases to Evaluate AIDS (IeDEA). (http://www.iedea.org/).
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Enhancing clinical and epidemiological HIV research in Europe through cohort collaboration
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STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cohort studies
PHACS AMP Up Protocol
Section/Topic
Title and abstract
Item
#
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Recommendation
Reported on page #
(a) Indicate the study’s design with a commonly used term in the title or the abstract
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(b) Provide in the abstract an informative and balanced summary of what was done and what was found
Introduction
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Background/rationale
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Explain the scientific background and rationale for the investigation being reported
Objectives
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State specific objectives, including any prespecified hypotheses
Study design
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Present key elements of study design early in the paper
Setting
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Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
Participants
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Methods
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Variables
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applicable
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Data sources/
measurement
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For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
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Bias
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Describe any efforts to address potential sources of bias
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Study size
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Explain how the study size was arrived at
Quantitative variables
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Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
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why
Statistical methods
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(a) Describe all statistical methods, including those used to control for confounding
(b) Describe any methods used to examine subgroups and interactions
(c) Explain how missing data were addressed
(d) If applicable, explain how loss to follow-up was addressed
(e) Describe any sensitivity analyses
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Results
Participants
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(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed
eligible, included in the study, completing follow-up, and analysed
(b) Give reasons for non-participation at each stage
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(c) Consider use of a flow diagram
Descriptive data
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(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
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(c) Summarise follow-up time (eg, average and total amount)
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Outcome data
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Report numbers of outcome events or summary measures over time
Main results
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(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence
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interval). Make clear which confounders were adjusted for and why they were included
(b) Report category boundaries when continuous variables were categorized
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(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Other analyses
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Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses
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Summarise key results with reference to study objectives
Interpretation
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Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
Generalisability
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Discuss the generalisability (external validity) of the study results
22
Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
Discussion
Key results
Limitations
similar studies, and other relevant evidence
Other information
Funding
which the present article is based
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*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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Following young people with perinatal HIV infection from
adolescence into adulthood: the protocol for PHACS AMP Up,
a prospective cohort study
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Journal:
Manuscript ID
Article Type:
Date Submitted by the Author:
Complete List of Authors:
BMJ Open
bmjopen-2016-011396.R1
Protocol
03-May-2016
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Tassiopoulos, Katherine; Harvard T.H. Chan School of Public Health,
Epidemiology
Patel, Kunjal; Harvard T.H. Chan School of Public Health, Epidemiology
Alperen, Julie; Harvard T.H. Chan School of Public Health, Epidemiology
Kacanek, Deborah; Harvard T.H. Chan School of Public Health, Biostatistics
Ellis, Angela; Frontier Science & Technology Research Foundation, Inc.
Berman, Claire; Harvard T.H. Chan School of Public Health, Epidemiology
Allison, Susannah; NIH, National Institute of Mental Health
Hazra, Rohan; NIH, Eunice Kennedy Schriver National Institute of Child
Health and Human Development
Barr, Emily; University of Colorado at Denver - Anschutz Medical Campus
Cantos, Krystal; Harvard T.H. Chan School of Public Health, Epidemiology
Siminski, Suzanne; Frontier Science & Technology Research Foundation,
Inc.
Massagli, Michael; Harvard T.H. Chan School of Public Health, Epidemiology
Bauermeister, Jose; University of Michigan School of Public Health, Health
Behavior and Health Education
Siddiqui, Danish; Tulane University Health Sciences Center, Pediatrics and
Infectious Diseases
Puga, Ana; Children's Diagnostic & Treatment Center
Van Dyke, Russell; Tulane University Health Sciences Center, Pediatrics
and Infectious Diseases
Seage III, George; Harvard T.H. Chan School of Public Health,
Epidemiology
Secondary Subject Heading:
Keywords:
HIV/AIDS
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<b>Primary Subject
Heading</b>:
Epidemiology
EPIDEMIOLOGY, PUBLIC HEALTH, World Wide Web technology <
BIOTECHNOLOGY & BIOINFORMATICS
Page 1 of 29
Title: Following young people with perinatal HIV infection from adolescence into adulthood: the
protocol for PHACS AMP Up, a prospective cohort study
Writing Team: Katherine Tassiopoulos DSc1, Kunjal Patel DSc1, Julie Alperen DrPH1, Deborah Kacanek ScD2,
Angela Ellis BS3, Claire Berman MS1, Susannah M. Allison PhD4, Rohan Hazra MD5, Emily Barr MSN6, Krystal
Cantos BA1, Suzanne Siminski MBA3, Michael Massagli PhD1, Jose Bauermeister PhD7, Danish Q. Siddiqui MPH8,
Ana Puga MD9, Russell Van Dyke MD8, George R. Seage III DSc1 for the Pediatric HIV/AIDS Cohort Study.
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, U.S.; 2Center
for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, U.S.;
3
Frontier Science and Technology Research Foundation, Inc, Amherst, New York, U.S.; 4Division of AIDS
Research, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, U.S.; 5Maternal
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and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland, U.S.; 6Department of Pediatric Infectious Diseases,
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University of Colorado, Children’s Hospital Colorado, Aurora, Colorado, U.S.; 7Department of Health Behavior and
Health Education, University of Michigan School of Public Health, Ann Arbor, Michigan, U.S.; 8Department of
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Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, U.S.; 9Children’s Diagnostic &
Treatment Center, Inc., Fort Lauderdale, Florida, U.S.
Katherine Tassiopoulos, DSc, MPH
Harvard T.H. Chan School of Public Health
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677 Huntington Ave., Kresge 817B
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Senior Research Scientist, Department of Epidemiology
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Corresponding author:
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BMJ Open
Boston, MA 02115
Phone: 617-432-3265; Fax: 617-566-7805
[email protected]
Keywords: adolescents, transition to adult clinical care, internet, longitudinal studies, perinatal HIV infection.
Word count: 3441
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BMJ Open
Collaborator Statement: This article is being submitted for the Pediatric HIV/AIDS Cohort Study.
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ABSTRACT
Introduction: The first generation of adolescents born with HIV infection has reached young
adulthood due to advances in treatment. It is important to continue follow-up of these individuals
to assess their long-term medical, behavioral and mental health and ability to successfully
transition to adulthood while coping with a chronic, potentially stigmatizing condition. To
accomplish this, and to maintain their interest in long-term research participation, we need to
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accommodate the changing lifestyles and interests of young adult study participants while
ensuring valid data collection. We report the protocol for PHACS (Pediatric HIV/AIDS Cohort
Study) AMP Up, a prospective cohort study enrolling young adult participants for long-term
follow-up.
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Methods and analysis: AMP Up is recruiting 850 young men and women 18 years of age and
older – 600 perinatally HIV-infected and a comparison group of 250 perinatally HIV-exposed,
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uninfected – at 14 clinical research sites in the United States and Puerto Rico. Recruitment began
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in April 2014 and is ongoing, with 305 participants currently enrolled. Planned follow-up is ≥ 6
years. Data is collected with a flexible hybrid of online and in-person methods. Outcomes
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include: transition to adult clinical care and retention in care; end-organ diseases; malignancies;
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metabolic complications; sexually transmitted infections; reproductive health; mental health and
neurocognitive functioning; adherence to antiretroviral treatment; sexual behavior and substance
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use; hearing and language impairments; and employment and educational achievement.
Ethics and dissemination: The study received ethical approval from the Harvard T.H. Chan
School of Public Health’s institutional review board (IRB) and from the IRBs of each clinical
research site. All participants provide written informed consent; for cognitively-impaired
individuals with legally authorized representatives, legal guardian permission and participant
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assent is obtained. Findings will be disseminated through peer-reviewed journals, conference
presentations and participant summaries.
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Strengths and limitations of this study
•
The PHACS AMP Up study will enable long-term follow-up of perinatally HIV-infected
(PHIV+) young adults for evaluation of a wide range of clinical, behavioral and mental
health outcomes, as well as transition to adult clinical care and adult functioning;
•
This study design allows flexibility in the transition from in-person to remote data
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collection, and can be adopted by other prospective epidemiologic studies concerned with
optimizing participant retention over the long-term;
•
Since AMP Up is enrolling young adults through the PHACS research clinical sites,
participants may be more likely to be adherent to clinical care and supportive services;
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young adults non-adherent or lost to care may not be well-represented.
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INTRODUCTION
The first generation of youth perinatally-infected with HIV (PHIV+) has reached late
adolescence and young adulthood. The Pediatric HIV/AIDS Cohort Study (PHACS), the largest
long-term study of perinatal HIV infection in the US, has advanced understanding of the effects
of antiretroviral medications (ARVs) and HIV infection on infectious and non-infectious
complications, and metabolic, growth, cardiovascular, neurodevelopmental, neurological and
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behavioral outcomes among youth and adolescents.(1-17) Continued follow-up into young
adulthood is needed in order to assess the longer-term effects of HIV and ARVs on these
outcomes,(18, 19) and to examine issues specific to these emerging young adults, including the
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effects of transitioning from pediatric to adult health care on clinical and behavioral outcomes
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and retention in care, the attainment of milestones of adulthood including higher education and
employment, reproductive outcomes, and the risks of HIV transmission to sexual partners and
offspring.
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The PHACS Adolescent Master Protocol (AMP) is a prospective cohort study that
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enrolled youth with PHIV+ and a comparison cohort of perinatally HIV exposed, uninfected
youth (PHEU) who were 7-16 years old at enrollment. Participants are followed at 14 research
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clinic sites across the United States including Puerto Rico. The first AMP participants reached 18
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years of age in 2009. While overall study retention remains strong, we found that older AMP
participants were being disproportionately lost to follow-up. The AMP Up protocol was
therefore conceived as a protocol tailored specifically to young adults, in order to maximize
validity of data collection as well as retention of participants in continued long-term follow-up.
Development of novel strategies to optimize sustained research participation is a critical
challenge for all long-term epidemiologic studies.(20, 21) For young adults involved in
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longitudinal studies since childhood, participation may become less appealing as they gain
independence, secure employment or attend college and thereby become less willing or able to
return to clinics for study visits. An additional disincentive exists if the participant does not have
a personal connection with the study and its long-term objectives. Youth whose caregivers had
originally provided consent and managed study visit appointments must consent for their own
continuing follow-up once they reach the age of majority. This provides them with the
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opportunity to decline further participation in research. There are also special challenges inherent
with following youth with chronic conditions into young adulthood, including fatigue after years
of time-intensive clinical and research study visits, and the transition away from their pediatric or
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adolescent clinics, where their research visits often take place, into adult care clinics.(22)
Investigators conducting long-term research of young people with chronic, serious conditions
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such as HIV infection must consider the inevitable transition away from the strong support
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systems that often exist for these youth in pediatric care but which may not exist in adult care
systems,(23-25) and the resulting effect on participants’ willingness and ability to continue to
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participate in research as adults.
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flexible study designs that are less time intensive and more accommodating of participants’
changing lifestyles than the clinic-based studies of their youth. A growing number of papers
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describe epidemiologic studies that use computer- and cell phone-based data collection
strategies.(26-31) In this paper we describe the rationale for and development of AMP Up, a
prospective cohort study that uses a flexible hybrid of online and in-person data collection to
follow PHIV+ and PHEU youth as they enter adulthood. AMP Up was designed to address the
primary scientific objective of defining the impact of HIV infection and antiretroviral therapy on
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young people with perinatal HIV infection as they transition into adulthood.
METHODS AND ANALYSIS
Assessing feasibility of AMP Up protocol
While national surveys suggest that most young adults in the US access and frequently use the
internet,(32) socioeconomic disparities in access persist.(33) Many PHACS participants come
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from socioeconomically disadvantaged backgrounds,(2) and PHACS research site staff indicated
that some study participants might have limited internet access. To determine whether PHACS
participants would be able to complete the online surveys through which a large proportion of
data in AMP Up would be collected, we conducted a feasibility study to evaluate the use of
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internet and mobile devices and willingness to participate in online research by youth and young
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adults seen at PHACS research clinics. The results of this anonymous survey are summarized in
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Table 1. Most individuals accessed the internet more than once a day, and the majority reported
being willing to participate in online research.
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Table 1. Feasibility study results: responses from anonymous survey on internet and cell phone use by
participants at PHACS clinical research sites, 2012-2013 (N=300)
Characteristic
N (%)
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Age range
Female sex
African American race
16-27 years
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212 (70.7)
Hispanic ethnicity
70 (23.3)
PHACS participant
134 (44.7)
Internet frequency in past 3 months
>once a day
<once a day/>=once a week
<once a week/nevera
225 (75.7)
56 (18.9)
16 (5.4)
Type of internet at home
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DSL/cable
Dial up
Wireless/3G/4G
Don’t know
No internet at home
Missing
76 (25.3)
1 (0.3)
125 (41.8)
43 (14.3)
30 (10.0)
25 (8.3)
Type of cell phone
Smart phone
Phone that can send/receive texts
No phone/cell phone doesn’t text
240 (80.1)
26 (8.8)
34 (11.1)
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Cell phone with unlimited internet
Yes
No
Don’t know
Cell phone doesn’t access internet
No cell phone
207 (69.3)
52 (17.6)
6 (2.0)
6 (2.0)
28 (9.1)
Willingness to participate in online researchb
Talk on cell phone about health or other parts of life
Go online to answer questions about health or other parts of life
Go to lab instead of clinic for blood draw and other medical tests
199 (66.5)
230 (77.7)
190 (64.0)
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Except where indicated, missing responses to individual questions range from 0-4.
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2 respondents reported no use of internet in past 3 months.
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Proportion responding ‘definitely would’ or ‘probably would’.
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We also considered the cognitive ability of PHACS participants to complete internet-
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information via an audio computer-assisted self-interview (ACASI), which is self-administered
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on a computer. If an ACASI is not completed at a given visit, the site records the reason. We
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(34) for AMP youth unable to complete any ACASI due to cognitive limitations and those who
completed one or more ACASI. The results the ACASI review are summarized in Table 2. The
vast majority of AMP participants have completed at least one ACASI; the few participants who
have not completed an ACASI because of cognitive limitations have significant impairments.
Table 2. Feasibility study results: ACASI completion and cognitive status of PHACS AMP
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participants
ACASI Completion Status
N (%)
Full Scale IQ Score,
mean (SD)a
P valueb
No ACASI completed due to cognitive
limitations
16 (2.6)
45.5 (8.4)c
<0.001
592 (97.4)
86.1 (15.3)c
≥ one ACASI completed
Abbreviations: ACASI, Audio computer-assisted self-interview.
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Full scale IQ score from Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV).
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From t-test.
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Due to missing WISC-IV, N for those without ACASI=12, N for ACASI completed =576.
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Based on the results of the internet use survey and the ACASI review, we expect that the
vast majority of eligible AMP Up participants will be able to complete the online surveys
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independently. However, as we describe below, we have incorporated accommodations for those
unable to do so.
AMP Up study design
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AMP Up is a prospective cohort study which conducts yearly online data collection for the
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majority of self-reported information, annual medical chart abstraction and STI specimen
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collection, and three in-person clinic visits at Entry, Year 3, and Year 6. Individual participants
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will be followed for a minimum of 6 years. The study is currently recruiting, with 305
individuals enrolled thus far.
Study population and inclusion criteria
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The eligible study population for AMP Up includes all PHIV+ and PHEU young adults 18 years
of age and older previously followed in AMP (including those lost to follow-up in AMP), along
with other PHIV+ young adults with available lifetime history of ARV use, CD4 and HIV-1
RNA, and major medical diagnoses. Perinatal HIV status must be documented in the patient’s
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medical chart. All eligible participants are recruited from one of 14 clinical research sites across
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at the clinical research sites. The targeted enrollment goal is 600 PHIV+ and 250 PHEU young
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adults.
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Evaluations and data collection methods
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The AMP Up protocol is measuring outcomes from a wide range of domains, including:
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transition to adult clinical care; employment and educational achievement; retention in health
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care; HIV end-organ disease outcomes (renal, hepatic, cardiac, pulmonary, and peripheral and
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central nervous system) and HIV-associated malignancies; metabolic complications
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(dyslipidemia, hypertension, insulin resistance, hyperlactatemia, excess adiposity and fat
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redistribution); sexually transmitted infections; reproductive health; mental health and
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neurocognitive functioning; adherence to antiretroviral treatment (ART); sexual behavior and
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substance use; and hearing and language impairments. The frequency of outcome and covariate
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measurement and data collection methods are summarized in Table 3, and then the specific
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information obtained with each method of data collection is described in detail.
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Study Visit
Data Collection
Assessment
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Method
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Entry
Yr 1
Yr 2
Yr 3
Yr 4 Yr 5
Yr 6
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(In(In(In54
clinic)
clinic)
clinic)
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Education, employment, housing
Online survey
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Health care utilization, transition to adult clinical
care
Online survey
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Social support, friendships, self-efficacy
Online
evaluation
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Quality of life
Online survey
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Physical activity
Online
evaluation
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Nutrition
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Online survey
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Medical and Neuropsychological Factors
Diagnoses1
Chart abstraction
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Chart abstraction
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Medications
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Height, weight, blood pressure1
Chart abstraction
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Body measurements
Clinic visit
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Reproductive health
Online survey
Neurocognitive functioning
Online
evaluation
Mental health: depression screen
Interview
Mental health: psychiatric diagnoses
Interview
Hearing
Online
evaluation
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Language
Interview
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Labs done for clinical care
Chart abstraction
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Laboratory biomarkers2
Clinic visit
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Sexually transmitted infections
Self-collection
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Repository samples3
Clinic visit
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Behavioral Factors
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10 Pregnancies, fractures, hearing problems, height and weight are also self-reported in annual online surveys.
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Venous lactate/pyruvate, renal biomarkers, cardiac biomarkers, fasting lipids, glucose, insulin.
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Data Collection Methods.
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Medical chart abstraction.
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laboratory measures, height, weight and blood pressure are abstracted from participants’ medical
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records.
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In-person clinic visits.
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Physical examinations, laboratory tests, interviewer-administered mental health evaluations
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(Client Diagnosis Questionnaire [CDQ];(35) Centers for Epidemiologic Studies Short
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Depression Scale [CES-D 10] (36)) and collection of repository storage specimens (blood, saliva,
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urine, vaginal swabs) are conducted. Cognitive function, hearing, emotional health and
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friendship are assessed via the online NIH Toolbox(37) and language is assessed with the
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interview-administered Clinical Evaluation of Language Fundamentals-4th edition (CELF).(38)
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Physical activity is evaluated with the online Block Physical Activity Screener.(39)
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Self-collection of sexually transmitted infection (STI) specimens.
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available in medical records during the 12 months prior to a study visit, urine and vaginal swabs
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are self-collected for STI testing at the local clinical laboratory. Additional urine and swab
samples are taken and sent to repository for further STI testing at a central research laboratory.
At in-person clinic visits, samples are self-collected at the clinic and at other time points are selfcollected either at the clinic or at home.
Online survey.
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The AMP Up online survey consists of a series of short modules with questions on the following
topics: employment/education/housing, health care, quality of life, sexual behaviors,
reproductive health, substance use, nutrition, and for PHIV+ participants, adherence to ART and
transition to adult clinical care. The survey also includes an acceptability question asking if
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participants would prefer to take the survey at home, in the clinic, or elsewhere, and a test
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question to assess how closely participants read the survey instructions. The survey ends with
optional questions to assess participants’ acceptability of the instrument.
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Input from members of the PHACS Young Adult Community Advisory Board (YACAB)
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emphasized strong preference for short surveys that did not repeat questions that were answered
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in earlier surveys. We therefore developed surveys that can be completed at one or multiple
sittings. Skip patterns are embedded within and also between surveys completed at different time
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points, allowing follow-up surveys to be tailored to each participant based on their responses to
previous surveys.
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Participants can opt to complete surveys at their study clinic or offsite. For individuals
with cognitive limitations who cannot respond to survey questions on their own, we developed a
shorter online instrument consisting of a subset of the modules (employment/education/housing,
health care utilization, medication adherence, and transition to adult HIV care) that can be
completed by their caregiver. Alternatively, participants who can respond on their own but
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cannot self-administer the online instrument can complete a similar, interviewer-administered
online survey that also includes the quality of life module.
While study clinics contact participants each year on the anniversary of their entry visit to
remind them to complete their surveys, participants are able to complete the surveys at any point
prior to the next entry visit anniversary. Upon completion, participants have the choice of a $75
virtual or physical gift card. This remuneration is provided in addition to funds provided by the
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clinical site to compensate for food, travel, or participation in other study activities.
The online surveys were piloted by research and clinic staff, YACAB members, and
other young adult volunteers from outside of PHACS. Surveys are thoroughly tested prior to
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implementation to ensure the proper placement and function of skip patterns. Responses to the
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surveys are regularly reviewed to allow for modification of potentially unclear questions.
Training and implementation
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participants, we created written instructions to guide them through important study processes,
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including study registration, specimen sample collection for STI testing, registration and
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navigation of the NIH Toolbox, and organization of the Entry visit. The importance of the inperson Entry visit is emphasized in the instructions, as it provides initial administration of the
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online survey in a familiar setting, and preparation for the Year 1 follow-up visit where the first
instance of remote data collection may take place.
Research sites’ role in data collection and participant engagement
Since staff at the pediatric/adolescent clinics are often an important part of participants’ systems
of support, research site staff have emphasized that their relationship with participants should be
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maintained during this potentially turbulent period. The AMP Up protocol was therefore
designed with flexibility in terms of the research sites’ role in data collection and participant
engagement, allowing participants to determine a comfortable pace by which to transition from
clinic-based research visits to remote online data collection. Initially, AMP Up site staff will be
integrally involved with all participants through study enrollment and completion of Entry visits.
For a certain subgroup of participants, this level of site involvement will continue throughout the
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duration of the protocol due to personal preference or because of lack of internet access or
cognitive limitations. However, it is anticipated that the ability and willingness of most young
adults to return to the clinic will diminish and eventually end due to competing priorities;
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therefore accommodations have been incorporated to allow for their continued study
participation entirely off-site, through chart abstraction, online data collection, and mailed-in
specimen collection.
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Sample size
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Our targeted sample size of 600 PHIV+ and 250 PHEU young adults will allow us to address
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AMP Up’s primary scientific objective of defining the impact of HIV infection and antiretroviral
therapy on young adults with perinatal HIV infection as they transition into adulthood. In the
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context of this study, we will be measuring many targeted outcomes, some continuous (e.g.,
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neurocognitive functioning defined as full scale IQ score) and some binary (insulin resistance,
retention in adult clinical care). For comparisons between PHIV+ and PHEU young adults,
continuous outcomes, the target sample size of 600 perinatally-infected versus 250 uninfected
participants for the AMP Up study provides 80% power to detect a difference in means for a
continuous outcome of 0.211 standard deviations based on a 2-sample t-test (assuming normality
holds), and 0.216 based on a non-parametric Wilcoxon rank sum test (for skewed outcomes) at
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alpha = 0.05. For example, if we were comparing the full-scale IQ scores of HIV infected vs.
uninfected participants and assumed a standard deviation of 15 points, we could detect a
difference of 3.16 points or more in the mean IQs. If we allow for possible loss to follow-up or
incomplete/missing assessments of 4% per year for infected and 6% per year for uninfected
participants for three years after enrollment into AMP Up is completed, then an adjusted sample
size of 530 HIV-infected vs. 208 HIV-uninfected participants provides 80% power to detect a
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difference of 0.229 standard deviations, or 3.44 points in mean IQ scores. Once we adjust for
potential confounders, we will typically lose some power so the minimum detectable difference
will usually increase.
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For binary outcomes, the minimum detectable odds ratios we can detect based on
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comparing HIV-infected vs. uninfected participants, at 80% power with a 0.05 significance level,
ranges from 1.57 to 2.64 depending on underlying rate of the event in the comparison (PHEU)
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cohort, which we have varied in these sample size calculations to be between 4% and 30%. For
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simplicity here, it is assumed that the event rate is higher in the HIV-infected group than the
PHEU group.
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those PHIV+ young adults who initiated ART before age 5 versus those who initiated ART at a
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later age. The detectable differences in means relative to the standard deviation that can be
detected assuming 530 PHIV+ participants (under an assumption of 4% loss per year) when two
subgroups of the PHIV+ participants are being compared ranges from 0.24 to 0.41, depending on
the sample percentages in each subgroup. When comparing proportions with events between two
subgroups, the minimum detectable odds ratios range from 1.63 to 4.01 depending on the percent
in each subgroup.
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Statistical analyses
Participants’ baseline characteristics (including demographics and clinical characteristics) will be
described using frequencies for categorical variables and means, medians, standard deviations
and interquartile range for continuous variables. Incidence estimates for outcomes will be
calculated under a Poisson distribution based on participant-years of follow-up.
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When evaluating associations between the many exposures and outcomes of interest in
this study, multivariable regression analyses will be conducted adjusting for potential
confounding factors. For cross-sectional associations, logistic and linear regression models will
be used. Cox proportional hazards models will be used for factors associated with incidence of
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commonly-occurring outcomes, and Poisson regression for incidence of outcomes that are
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observed to occur less frequently. For evaluation of factors associated with changes in outcomes
over time, generalized estimating equation (GEE) or mixed effects models will be employed.
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terms to the multivariable regression models. A probability level of 0.05 will be used for all
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analyses.
All analyses will be conducted using SAS Version 9.2 (SAS Institute Inc., Cary, NC).
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ETHICS AND DISSEMINATION
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The AMP Up protocol was approved by the Harvard T.H. Chan School of Public Health’s
Institutional Review Board (IRB) as well as the IRBs at the 14 participating sites. Participants
provide written informed consent; for cognitively-impaired individuals with legally authorized
representatives, legal guardian permission and participant assent is obtained.
To protect participant confidentiality, in addition to an anonymized Participant Identifier
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assigned to all PHACS participants, AMP Up participants are assigned a Personal Identification
Number and Keyword to enter and submit online survey data. Written instructions were also
developed for participants to provide steps to maintain their privacy when participating in webbased research. DatStat,(40) which hosts the AMP Up online surveys, maintains stringent levels
of encryption and data storage that exceed both industry standards for Internet security and IRB
standards for the protection of research participants and electronic records. DatStat’s technology
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platform, including servers, databases, and web presences, employ multiple layers of security
features to protect research participants and their data.
Dissemination
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The findings from this study will be disseminated through peer-reviewed journals, national and
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international conference presentations, and to study participants through participant summaries
that are presented in YACAB newsletters and in a recently-developed participant website.
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DISCUSSION
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by YACAB members and site staff. This connection may minimize the participation and
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retention issues experienced by other epidemiologic studies recruiting and following participants
entirely online.(41) The long-term success of AMP Up will be tested as more participants
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relocate, attend college, transfer their clinical care to adult clinics (a process typically completed
by age 25), or take on work and family responsibilities that preclude them from completing study
assessments in the clinic at which they enrolled in AMP Up. While our initial success may hinge
upon the strong connections participants have with their sites, in order to successfully transition
them to remote visits we will need to encourage direct connections between participants and the
PHACS study itself. For this reason we are taking steps to strengthen the association AMP Up
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participants have with PHACS. This began with the involvement of AMP participants in the
development of AMP Up, and has continued with the development of the YACAB and of the
participant website, through which participants link to their online surveys, access information
on health, education and housing opportunities, and connect with other study members.
Given it will be important for the majority of AMP participants to successfully enroll into AMP
Up as they reach 18 years of age, we are beginning to examine enrollment trends and reasons for
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not enrolling. Additional challenges in recruitment and study retention will arise when AMP Up
opens enrollment to PHIV+ young adults not previously involved in research protocols at our
research clinics. We are exploring methods to offer web-based informed consent forms,
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enrollment and medical record release authorizations for these potential participants. The close
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connection our participants experience with their clinic sites also emphasizes an important
limitation of our study. Since we are enrolling young adults through these clinical sites, our
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participants may be more likely to be adherent to clinical care and supportive services; young
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adults who are non-adherent or lost to care may not be well-represented in our cohort.
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In some aspects the first generation of perinatally HIV-infected youth is unique. Many of
these young people were born before the advent of effective antiretroviral therapy and were not
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expected to live past childhood. This expectation may have profound consequences for their
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transition into young adulthood, a transition which is of particular research interest both
domestically and internationally. To potentiate the opportunity to collaboratively study
transition, we have shared the AMP Up protocol and online survey instrument with other, global
networks whose aims include an examination of the transition into adult clinical care for young
people infected with HIV, including the International Epidemiologic Databases to Evaluate
AIDS (IeDEA) (42) and EuroCoord.(43) The design of AMP Up, which allows flexibility in the
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transition from in-person to remote data collection, can also enhance long-term research
possibilities for a broader set of studies. Investigations undertaking long-term follow-up of
young adults with chronic conditions, including birth or early childhood cohorts, or more
generally, any epidemiologic studies for which long-term success is contingent upon the ability
to retain participants’ interest and long-term commitment, can potentially benefit from adopting
this study design.
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Author contributions: Author KT was integrally involved in conception and design of the
protocol and drafting of the manuscript; authors GS, RVD, RH and SA were integrally involved
in conception and design of the protocol, reviewed the manuscript and provided revisions; author
KP was involved in design of the protocol and provided critical input on content and
organization of the paper; author JA was involved in design and implementation of the protocol,
wrote segments of the manuscript’s Methods section and provided critical feedback on the
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manuscript in full; authors KC, SS, MM, AE, CB and DK were involved in development of one
or more of the protocol’s data collection instruments, reviewed the manuscript and provided
important revisions; authors JB and DS provided important insight as to the structure and content
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of the online survey instrument, reviewed and revised the manuscript, and authors EB and AP
participate in data acquisition and reviewed and revised the manuscript.
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Funding: The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice
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Kennedy Shriver National Institute of Child Health and Human Development with co-funding
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from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious
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Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National
Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other
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Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of
Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism,
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through cooperative agreements with the Harvard T.H. Chan School of Public Health
(HD052102) and the Tulane University School of Medicine (HD052104).
Note: The conclusions and opinions expressed in this article are those of the authors and do not
necessarily reflect those of the National Institutes of Health or U.S. Department of Health and
Human Services.
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BMJ Open
Acknowledgements:
We thank the children and families for their participation in PHACS, and the individuals and
institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy
Shriver National Institute of Child Health and Human Development with co-funding from the
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National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the
Office of AIDS Research, the National Institute of Mental Health, the National Institute of
Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication
Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and
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Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through
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cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102)
(Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University
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School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal
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Investigators: Kenneth Rich, Ellen Chadwick; Project Director: Patrick Davis). Data
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management services were provided by Frontier Science and Technology Research Foundation
(PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat,
Inc (PI: Julie Davidson).
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The following institutions, clinical site investigators and staff participated in conducting PHACS
AMP and AMP Up in 2015, in alphabetical order: Ann & Robert H. Lurie Children’s
Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter;
Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris;
Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron;
23
BMJ Open
Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Patricia Garvie,
James Blood; Children’s Hospital, Boston: Sandra Burchett, Nancy Karthas, Betsy Kammerer;
Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; Rutgers - New Jersey
Medical School: Arry Dieudonne, Linda Bettica, Susan Adubato; St. Christopher’s Hospital
for Children: Janet Chen, Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant; St. Jude
Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan
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Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera;
Tulane University Health Sciences Center: Margarita Silio, Medea Jones, Patricia Sirois;
University of California, San Diego: Stephen Spector, Kim Norris, Sharon Nichols;
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University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Alisa Katai,
Jennifer Dunn, Suzanne Paul; University of Miami: Gwendolyn Scott, Patricia Bryan, Elizabeth
Willen.
Conflicts of Interests: None reported.
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Alperen J, Brummel S, Tassiopoulos K, et al. Prevalence of and risk factors for substance use
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STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cohort studies
PHACS AMP Up Protocol
Section/Topic
Title and abstract
Item
#
1
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Recommendation
Reported on page #
(a) Indicate the study’s design with a commonly used term in the title or the abstract
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(b) Provide in the abstract an informative and balanced summary of what was done and what was found
Introduction
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Background/rationale
2
Explain the scientific background and rationale for the investigation being reported
Objectives
3
State specific objectives, including any prespecified hypotheses
Study design
4
Present key elements of study design early in the paper
Setting
5
Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
Participants
6
(a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up
Methods
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6
9-10
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collection
2
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9-10
(b) For matched studies, give matching criteria and number of exposed and unexposed
Variables
7
Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
10-13
Data sources/
measurement
8*
For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
10-13
Bias
9
Describe any efforts to address potential sources of bias
18-19
Study size
10
Explain how the study size was arrived at
Quantitative variables
11
Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
on
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why
Statistical methods
12
(a) Describe all statistical methods, including those used to control for confounding
(b) Describe any methods used to examine subgroups and interactions
(c) Explain how missing data were addressed
(d) If applicable, explain how loss to follow-up was addressed
(e) Describe any sensitivity analyses
16-17
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Results
Participants
13*
(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed
eligible, included in the study, completing follow-up, and analysed
(b) Give reasons for non-participation at each stage
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(c) Consider use of a flow diagram
Descriptive data
14*
(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
9-13
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(b) Indicate number of participants with missing data for each variable of interest
(c) Summarise follow-up time (eg, average and total amount)
ee
Outcome data
15*
Report numbers of outcome events or summary measures over time
Main results
16
(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence
rr
interval). Make clear which confounders were adjusted for and why they were included
(b) Report category boundaries when continuous variables were categorized
ev
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Other analyses
17
Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses
18
Summarise key results with reference to study objectives
Interpretation
20
Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
Generalisability
21
Discuss the generalisability (external validity) of the study results
22
Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
Discussion
Key results
Limitations
similar studies, and other relevant evidence
Other information
Funding
which the present article is based
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*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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BMJ Open
Following young people with perinatal HIV
infection from adolescence into adulthood: the
protocol for PHACS AMP Up, a prospective
cohort study
Katherine Tassiopoulos, Kunjal Patel, Julie Alperen, Deborah Kacanek,
Angela Ellis, Claire Berman, Susannah M Allison, Rohan Hazra, Emily Barr,
Krystal Cantos, Suzanne Siminski, Michael Massagli, Jose Bauermeister,
Danish Q Siddiqui, Ana Puga, Russell Van Dyke and George R Seage III
BMJ Open 2016 6:
doi: 10.1136/bmjopen-2016-011396
Updated information and services can be found at:
http://bmjopen.bmj.com/content/6/6/e011396
These include:
References
This article cites 34 articles, 8 of which you can access for free at:
http://bmjopen.bmj.com/content/6/6/e011396#BIBL
Open Access
This is an Open Access article distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on different terms,
provided the original work is properly cited and the use is non-commercial.
See: http://creativecommons.org/licenses/by-nc/4.0/
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