Bioethics Paper

Received: 8 December 2017 Revised: 5 April 2018 Accepted: 11 April 2018

DOI: 10.1002/pbc.27228

Pediatric
Blood &
Cancer The American Society ofPediatric Hematology/Oncology

R E S E A R C H A R T I C L E

Sickle Cell Clinical Research and Intervention Program
(SCCRIP): A lifespan cohort study for sickle cell disease
progression from the pediatric stage into adulthood

Jane S. Hankins1 Jeremie H. Estepp1 Jason R. Hodges1

Martha A. Villavicencio1 Leslie L. Robison2 Mitchell J. Weiss1 Guolian Kang3

Jane E. Schreiber4∗ Jerlym S. Porter4 Sue C. Kaste5,6,7 Kay L. Saving8

Paulette C. Bryant9 Jeffrey E. Deyo10 Kerri A. Nottage11 Allison A. King12

Amanda M. Brandow13 Jeffrey D. Lebensburger14 Oyebimpe Adesina15

Stella T. Chou16 Babette S. Zemel17 Matthew P. Smeltzer18 Winfred C. Wang1

James G. Gurney18

1Department of Hematology, St. Jude Children’s Research Hospital, Memphis, Tennessee

2Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, Tennessee

3Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, Tennessee

4Department of , St. Jude Children’s Research Hospital, Memphis, Tennessee

5Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee

6Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, Tennessee

7Department of Radiology, University of Tennessee Health Science Center, Memphis, Tennessee

8OSF Healthcare Children’s Hospital of Illinois, University of Illinois College of Medicine, Peoria, Illinois

9Department of Pediatric Hematology and Oncology, Novant Health Hemby Children’s Hospital, Charlotte, North Carolina

10Department of Pediatric Hematology/Oncology, Our Lady of the Lake Children’s Hospital, Baton Rouge, Louisiana

11Janssen Research & Development, Raritan, New Jersey

12Program in Occupational Therapy, Washington University in St. Louis, St. Louis, Missouri

13Section of Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin

14Department of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama

15Division of Hematology, University of Washington, Seattle, Washington

16Division of Hematology and the Apheresis Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

17Department of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

18School of Public Health, University of Memphis, Memphis, Tennessee

Correspondence

JaneS.Hankins,DepartmentofHematology,St.

JudeChildren’sResearchHospital,332Danny

ThomasPlace,MailStop800Memphis,TN

38105.

Email: [email protected]

∗JaneE.Schreiber’snewaffiliationiswithinthe

DepartmentofChildandAdolescentPsychiatry

andBehavioralSciences,Children’sHospitalof

Philadelphia,Philadelphia,Pennsylvania.

Grantsponsor:ALSAC

Abstract
Background: Previous natural history studies have advanced the understanding of sickle cell

disease (SCD), but generally have not included sufficient lifespan data or investigation of the

role of genetics in clinical outcomes, and have often occurred before the widespread use of

disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To fur-

ther advance knowledge of SCD, St. Jude Children’s Research Hospital established the Sickle Cell

ClinicalResearchandInterventionProgram(SCCRIP),toconductresearchinaclinicallyevaluated

cohort of individuals with SCD across their lifetime.

Abbreviations: CDC, Centers for Disease Control and Prevention; EMR, electronic medical record; Hb, hemoglobin; NIH, National Institutes of Health; PRO, patient-reported outcome; SCCRIP,

Sickle Cell Clinical Research and Intervention Program; SCD, sickle cell disease; St. Jude, St. Jude Children’s Research Hospital

Pediatr Blood Cancer. 2018;65:e27228. c© 2018 Wiley Periodicals, Inc. 1 of 12wileyonlinelibrary.com/journal/pbc
https://doi.org/10.1002/pbc.27228

http://orcid.org/0000-0003-4439-7321

http://crossmark.crossref.org/dialog/?doi=10.1002%2Fpbc.27228&domain=pdf&date_stamp=2018-05-24

2 of 12 HANKINS ET AL.

Procedures: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with

SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial,

psychosocial, and health outcomes data. Biological samples are banked for future genomics and

proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific

working groups and is opened to the research community for partnerships.

Results: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study

(860 children and 184 adults), with 11,915 person-years of observation. Population demographics

included mean age at last visit of 11.3 years (range 0.7–30.1), 49.8% females, 57.7% treated with

hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0-

thalassemia, 25.7% HbSC, 8.4% HbsB+-Thalassemia, 1.7% HbS/HPFH, and 1.2% other.

Conclusions: The SCCRIP cohort will provide a rich resource for the conduct of high impact multi-

disciplinary research in SCD.

K E Y W O R D S

disease-modifying therapy, natural history, sickle cell anemia

1 INTRODUCTION

An estimated 100,000 individuals in the United States live with sickle

cell disease (SCD),1 and worldwide an estimated 300,000 babies are

born with the disease each year.2,3 The clinical consequences are

severe and include recurrent episodes of acute severe pain, chronic

pain, cerebrovascular events, progressive organ damage, and early

death.

In the United States and other high-income countries, survival

to adulthood of children with SCD has increased over the past five

decades from 50% to greater than 95%.1,4–7 This survival increase is

primarily due to mandatory newborn screening, infection prevention

with penicillin prophylaxis and pneumococcal vaccination, improved

supportive care, and increased use of disease-modifying therapies,

such as hydroxyurea and chronic erythrocyte transfusions.8–13 How-

ever, accumulation of end-organ damage to the heart, lungs, brain,

kidneys, and bones continues to occur.14 This organ damage man-

ifests in young adults with higher rates of acute health utilization,

emergency room reliance, and hospitalization.15,16 Disease-related

mortality rises in young adults and the median age of death among

adults with hemoglobin (Hb) SS and HbS?0-thalassemia is mid to late

40s.1,17,18

Understanding the natural history of SCD across the lifespan

in the contemporary medical environment is crucial, because the

substantial improvement in pediatric survival contrasts with lesser

gains in health outcomes among adults. A particular challenge is

the assessment of clinical outcomes during the vulnerable period of

transition from the pediatric to the adult care setting. During this

transitional period, deficits in preparation, planning, care coordi-

nation, and available skilled adult care providers lead to low rates

of engagement in adult care and interrupt care continuity.19,20

Without an appropriate infrastructure to collect longitudinal

health outcomes data as children age into adulthood, informa-

tion will be limited, insufficient to answer questions examining

disease progression, and unlikely to stimulate progress in the

field.

1.1 Knowledge gained from early SCD cohorts

Three early cohort studies have informed much of our understanding

of the epidemiology and natural history of SCD, although each began

prior to the advent and widespread use of current disease-modifying

therapies; these are the Jamaican Cohort Study (1973–1981),21,22

the Cooperative Study of Sickle Cell Disease (1979–1999),23,24 and

the Dallas cohort study (1983 to present)25 (Table 1). These stud-

ies provided the foundation for understanding variations in the dis-

ease severity phenotype, acute complications of SCD, survival rates,

mortality risks, laboratory values, and the basis for sepsis and stroke

prevention.6,26–41 Over the past decade, clinical trials have demon-

strated the benefit of hydroxyurea 42,43 and erythrocyte transfusions

for stroke prevention, building on the knowledge from earlier cohort

studies. More recently, smaller retrospective and prospective cohort

studies have shown that hydroxyurea may reduce mortality and pre-

vent organ damage.44–48 Thus, SCD cohort studies that factor in long-

term health effects of disease-modifying therapies, such as hydrox-

yurea and chronic erythrocyte transfusions begun in childhood, should

be the gold standard for observational and interventional research

studies in the modern era.

From our current perspective, important limitations of these ear-

lier cohorts were the lack of sufficient longitudinal data to cover the

full lifespan (i.e., studies were focused on either children or adults), the

limited genotype–phenotype studies, and the insufficient exposure to

disease-modifying therapies. The long-term follow-up of the phase III

BABY HUG study (NCT00890396) has been monitoring the long-term

effects of hydroxyurea therapy, but this cohort study is relatively small

and data collection has ended. More recent cohorts that have included

patients exposed to disease-modifying therapies have lacked sufficient

internalcomparativegroups,suchaspatientsnotexposedtotherapies,

limiting their external validity.

1.2 Scientific importance of SCCRIP

Longitudinal evaluation of outcomes throughout the lifespan will

enhance our understanding of disease progression, identify early

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4 of 12 HANKINS ET AL.

predictors of later outcomes, elucidate the roles of genetic, pro-

teomics, and environmental factors on health outcomes, and define

the long-term impact of therapies. To address these goals and circum-

vent the limitations of prior studies, we initiated the Sickle Cell Clinical

Research and Intervention Program (SCCRIP, NCT 02098863). Here

we describe the design of SCCRIP, including its systematic approach

to data abstraction according to developmental stage, particularly the

transition from pediatric to adult care, and how the phenotype data

are being classified in a fashion that can be compared across multiple

institutions.

2 METHODS

2.1 Study aims and design

Initiated in April 2014, SCCRIP is a cohort study with prospective

follow-up, ongoing data accrual, and retrospective collection of exten-

sive clinical history. The overarching goal of SCCRIP is to under-

stand the clinical, biological, and psychosocial progression of SCD

and factors contributing to early mortality across the lifespan, with

the ultimate goal of facilitating effective therapies. The objectives

are two-fold: (1) to establish a longitudinal clinical cohort of patients

with SCD; and (2) to establish a biorepository of DNA, urine, and

plasma.

2.2 SCCRIP participating sites

SCCRIP enrolls patients from five institutions (Figure 1). These sites

were chosen based on the size of their SCD population, their relation-

ship with St. Jude Children’s Research Hospital (St. Jude), and ability to

perform uninterrupted data collection from birth through adulthood.

St. Jude, the clinical and data coordinating site, treats 850 children

with SCD from birth to age 18 years. Through Tennessee and Missis-

sippi State Health Department contracts, St. Jude has been the referral

treatment center for new SCD cases from west Tennessee and north

Mississippi, diagnosed through the newborn screening programs in

those states, for the past 20 years. Following referral to St. Jude, 100%

of infants with newly diagnosed SCD are seen in the SCD clinic and

initiate penicillin prophylaxis within 2 months.49 Care provided by St.

Jude is free (including medications), and support with transportation

and meals is provided during regular and study visits.50 Approximately

80% of St. Jude patients transfer care to the Comprehensive Sickle

Cell Program in the partnering Methodist University Hospital, ensur-

ing care continuity and uninterrupted research data ascertainment.51

The Methodist University Hospital is located 2.5 miles from the St.

Jude campus, and currently cares for 300 adults, of whom approxi-

mately90%areformerSt.Judepatients.Aftertransitionofcare,adults

are followed similarly to children, with health-maintenance visits at

least twice per year when chronic end-organ damage is performed as

standard of care. The remaining three sites belong to the St. Jude Affil-

iate Program and share the purpose of extending protocol-structured

treatment and research through clinical, research, and academic part-

nerships. Support with meal expenses and transportation costs related

FIGURE 1 SCCRIP participants’ geographical distribution. The
1,044 SCCRIP participants are distributed among the following five
sites in four states: two in Memphis, TN (St. Jude Children’s Research
Hospital and Methodist University Hospital), one in Peoria, IL (OSF
Healthcare Children’s Hospital of Illinois), one in Charlotte, NC
(Novant Health Hemby Children’s Hospital), and one in Baton Rouge,
LA (Our Lady of the Lake Children’s Hospital)

to study visits are provided by St. Jude. Collectively, these five insti-

tutions care for approximately 1,600 individuals with SCD and con-

tribute geographic, social, and environmental diversity to the SCCRIP

clinical cohort.

2.3 SCCRIP organizational structure

The SCCRIP multidisciplinary research team blends expertise in

pediatric and adult hematology, nephrology, pulmonology, cardiology,

radiology, pain, psychology, bone metabolism, transfusion medicine,

epidemiology, genetic epidemiology, biostatistics, social sciences, com-

putational biology, bioinformatics, geocoding, and data management.

Research-related activities within SCCRIP are divided into nine Work-

ing Groups, which focus on questions related to a specific organ sys-

tem, disease complication, or therapy, and provide primary oversight

for the development and conduct of research initiatives. Investiga-

tors seeking to answer specific research questions are required to

collaborate with the appropriate Working Group(s) and complete a

concept proposal (Supplementary Material S1) that is reviewed and

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HANKINS ET AL. 5 of 12

FIGURE 2 SCCRIP organizational structure. SCCRIP’s scientific ini-
tiatives are driven by the Working Groups, which are composed of St.
Jude and external investigators. The Steering Committee vets all con-
cept proposals from the Working Groups and follows recommenda-
tions from the Executive Committee regarding major study delibera-
tions. Plans are in place to expand SCCRIP collaboration to the SCD
community by allowing access to the SCCRIP resource to external col-
laborators beyond current collaborators

approved by the Steering Committee, comprised of SCCRIP investi-

gators. The SCCRIP Steering Committee evaluates the quality of the

science,design,andanalyticalplanforeachnewresearchproposal.The

Executive Committee is responsible for major deliberations and con-

flict resolution within SCCRIP. A number of committees provide over-

sight of activities related to the publication of results from SCCRIP,

and access and utilization of the SCCRIP resource. An external advi-

sory committee, consisting of pediatric oncologists, pediatric hema-

tologists, epidemiologists, and biostatisticians, provides input into the

currentandfutureactivities.Inthefuture, it isourplantoopenSCCRIP

data access to the broader SCD research community. In this model,

non-SCCRIP investigators will have access to SCCRIP data and sam-

ples, once approved by the Steering Committee. Figure 2 outlines the

organizational structure for SCCRIP.

2.4 Subject sampling and follow-up strategy

Participants are prospectively recruited if they have a diagnosis of

SCD of any type and receive treatment at one of the five participat-

ing sites. Participants are not selected based on disease severity or

treatment exposure. Prospective data collection starts at study enroll-

ment, but existing clinical and laboratory data, when available, are ret-

rospectively collected from the point of first encounter with the health

care system. This strategy for data collection allows for reconstruc-

tion of the participant’s entire medical and treatment history regard-

less of the age at enrollment. There is no final enrollment goal for the

study. Rather, we plan to approach and enroll the entire SCD popu-

lation managed by all participating sites. Once enrolled, participants

are categorized according to one of the following six developmental

age cohorts: newborn (0 to 5.9 months), infant-toddler (6 months to

5.9 years), school age child (6–11.9 years), adolescent (12–17.9 years),

young adult (18–24.9 years), and older adult (25 and older). This cohort

categorization allows for the classification of clinical and laboratory-

based variables according to age, facilitating both longitudinal and

age-stratified analyses.

2.5 Data variables

All clinical and laboratory assessments performed as standard of care

for SCD are defined by national standards or institutional clinical

practice.52 SCCRIP data are collected at standard intervals and classi-

fied into the following three tiers (Table 2): universal (e.g. Hb fraction-

ation, urine microalbumin), risk-based (e.g. transcranial Doppler ultra-

sound in children aged 2–16 years with HbSS and HbS0-thalassemia),

and symptom-based (e.g. magnetic resonance imaging to investigate

osteonecrosis due to prolonged joint pain, impaired range of motion,

and debility). Healthcare utilization (e.g. admission, acute care vis-

its) and educational attainment data are also collected for the entire

cohort. Additionally, participants are offered optional research activ-

ities every 6 years, including banking of biospecimens (urine, plasma,

and DNA), measurement of high sensitivity C-reactive protein, and

assessment of health-related quality of life using the PedsQLTM

instrument (generic, SCD, and multidimensional fatigue modules, and

the corresponding adult versions once participants reach adult age)

(Table 2).53–55 After transition from pediatric to adult clinical care,

SCCRIP adult participants return to St. Jude every 6 years for compre-

hensive data collection to assess disease status.

2.6 Consenting process and institutional review

board oversight

Subjects are approached during nonacute health maintenance visits

and informed consent is obtained directly from participants who are

18 years of age and older or their legal guardian, if subjects are minors.

Verbal assent is obtained from minors who are between the ages of 7

and 13 years, and signed assent from those between 14 and 17 years

of age. When participants reach the age of majority (18 years), they are

reconsented into the study.

A tiered consent provides subjects with opt-in/opt-out choices

for participating in the research activities beyond the collection

of past and future standard of care data (Table 2, optional evalua-

tions). Extensive discussion regarding future genetic testing takes

place during informed consent, including the information that these

studies are performed in a laboratory not approved by Clinical

Laboratory Improvement Amendments and will not be returned to

the participants. Opt-in/opt-out choices for recontacting partici-

pants due to incidental findings are provided. Examples of potential

future research with subjects’ biospecimens and the potential

risks to loss of privacy are discussed in the context of genomics

research. Public sharing of genetic data will occur according to

the National Institutes of Health (NIH) Genomic Data Sharing Policy

(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html)

for NIH-funded projects. Access requests from non-SCCRIP investiga-

tors for combined genetic and phenotypic data for hypothesis-driven

research may be approved after completion of a concept proposal

(Supplementary Material S1). The SCCRIP Steering Committee will

evaluate external concepts on the scientific significance, innovation,

and approach of their proposed project as well as the investigative

team, research environment, and funding availability.

https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html

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HANKINS ET AL. 7 of 12

FIGURE 3 Consort diagram for SCCRIP. The overall acceptance par-
ticipation rate is 92.3% and acceptance of optional research activities
(biobanking of DNA, urine, and plasma) is 97.9%

3 DATA MANAGEMENT

SCCRIP study staff document all interactions with eligible and enrolled

participants through an electronic tracking database. The program

generates reports that summarize enrollment and study-related

information and notifies study staff of upcoming study events for

each subject, such as time to complete age of majority consents and

time to enter study-specific orders. Data sources for SCCRIP include

patient-reported outcome (PRO) surveys and data electronically or

manually abstracted from medical charts. PRO data are gathered

electronically using a mobile device (tablet), and stored in an electronic

data management system, to later be extracted and deposited into

the SCCRIP database. Clinical data are extracted in a table format

from each site’s electronic medical record (EMR, Cerner R© or Epic R©

software systems) through a series of queries or custom reports, which

local information technology staff develop and execute regularly. Data

from external sites are securely transmitted and uploaded to St. Jude

regularly using Health Insurance Portability and Accountability Act–

compliant protocols. Participants’ addresses are geocoded annually

using ArcGIS (Esri, Redlands, CA) to determine the socio-economic

characteristics of participants’ neighborhoods and proximity to both

resources (e.g. food access, parks, schools) and environmental hazards

(e.g. interstates, airports). Once collected, SCCRIP phenotype data

undergo an additional iterative step to match the clinical events

according to the consensus measures for phenotypes and exposures

(PhenX) toolkit. (https://www.phenxtoolkit.org).56 Approximately

80% of SCCRIP and PhenX data are concordant (Supplementary

Table S1).

To facilitate data analyses, an annual data freeze is performed. For

each data domain, computer programs (1) download and perform qual-

ity control checks; (2) merge data from disparate sources; (3) import

relevant data fields from other external sources; and (4) save a sin-

gle analytical dataset containing all required data elements. SCCRIP

data management operations require a substantial amount of human

resources. Currently, the study has two data managers who perform

data extraction, data structuring, and data cleaning and seven research

coordinators who perform patient consenting, PRO collection, and

manual data abstraction, and help coordinate data transfer from all

sites.

3.1 Data analysis plan and lost-to-follow-up tracing

The assigned study statistician will conduct the analytical plan and

return aggregate results and graphical display of data to the inves-

tigators for manuscript or grant preparation. A system to trace

lost-to-follow-up from death is in place through annual searches of

the National Death Index, a program maintained by the National

Center for Health from the Centers for Disease Control

and Prevention (CDC). These annual searches will allow for mor-

tality ascertainment (date and cause of death) for lost-to-follow-up

cases.

4 RESULTS

4.1 Participant enrollment

As …