Hydroxyurea Adherence for Personal Best in Sickle Cell Disease (HABIT): Efficacy Trial
Phase: NA
Conditions: Sickle Cell Disease
Sponsor: Columbia University

 
 
 
 
 
 
Hydroxyurea Adherence for Personal Best in Sickle Cell Disease (HABIT): 
Efficacy Trial 
 
 
NCT03462511 
 
July 14, 2020 

SPECIFIC AIMS 
Sickle cell disease (SCD) is a major chronic illness affecting approximately 100,000 Americans of African 
descent, including Caribbean Latinos and other underserved ethnicities.1,2 An inherited blood disease, SCD is 
characterized by fatigue, painful crises, organ damage, reduced quality of life (QOL) and high health care costs 
and shortened lifespan.3-6 The sole FDA-approved drug for SCD therapy is hydroxyurea (HU); its use is 
recommended as standard practice.7 HU markedly reduces symptoms, morbidity and mortality, improves QOL, 
decreases health care cost, and may protect against cumulative disease burden.7 HU induces a dose-
dependent increase in fetal hemoglobin (HbF), an effect that is largely responsible for its impact.8,9 Despite 
benefits of HU, adherence in adolescents and young adults is often poor.10-15 Barriers to adherence, especially 
among underserved populations, include cultural misalignment with medical staff,16-18 incomplete knowledge of 
drug benefit,19-21 logistic impediments to prescription refill.22 Poor adherence is linked to inadequate integration 
of adherence into a daily medication habit.23 Barriers to medication adherence are common in youth with 
chronic illness24-28 and a source of racial/ethnic disparities in underserved communities.29,30 The goal of this 
multi-site study is to assess the efficacy of our recently piloted intervention, HABIT, which was 
designed to improve self-managed adherence to HU therapy while developing a daily medication habit 
in youth with SCD.  
 
The scientific premise and experience for the proposed study is based on our 2-site randomized feasibility trial 
of “HABIT” (R21NR013745), a 6-month intervention delivered by community health workers (CHWs), 
augmented by tailored text messages sent to subjects.31 A multi-ethnic sample of 28 youth-parent dyads (youth 
ages 10-18 years) participated in this study. Eligible youth had ≥20% decrease from maximum HU-induced 
HbF levels, “Personal Best.” The intervention was both feasible and acceptable, and sufficiently effective on 
our primary outcome of medication adherence - operationalized by two objective measures.  Building on these 
promising results and partnering with three additional clinical sites, we propose a larger 5 site randomized 
controlled trial of 104 youth-parent dyads to test the efficacy of the HABIT intervention.  
 
Study aims are to: 
Aim 1: Improve daily HU adherence, the primary outcome operationalized two ways: biomarker (approach or 
exceed a historical Personal best HbF) and pharmacy refill (proportion of days covered).  
Hypothesis 1: Compared to the control group, youth-parent dyads randomized to the intervention will improve 
medication adherence at 6 months, with sustained improvement at 12 months. 
 
Aim 2: Improve quality of life and self-management responsibility measured by three secondary outcomes: 
generic and disease-specific QOL and parent/youth concordance regarding delegation of self-management 
responsibility. Hypothesis 2: Compared to the control group, dyads randomized to the intervention will report 
improved quality of life and self-management responsibility concordance at 6 months, with sustained 
improvement at 12 months. 
 
Aim 3: Improve health status measured by two secondary outcomes: acute hospital use (12 month hospital 
length of stay, admissions and emergency room visits) and self-reported disease symptoms (fatigue, pain 
interference and intensity). Hypothesis 3.1: Compared to the control group, youth-parent dyads randomized to 
the intervention group will demonstrate decreased acute hospital use at 6 months, with sustained improvement 
at 12 months. Hypothesis 3.2: Compared to the control group, dyads randomized to the intervention group will 
report decreased disease symptoms at 6 months, with sustained improvement at 12 months. 
 
Aim 4: Qualitatively describe impact and sustainability of the intervention on developing a daily medication HU 
habit from the perspectives of the community health workers (CHWs) and youth-parent-dyads using focus 
group and individual interviews (exploratory aim).   
 
Impact: Adherence to daily medications is a challenge for most youth with chronic health conditions and poor 
adherence is common.24  Identifying successful ways to improve adherence to HU through developmentally 
appropriate self-management not only has the potential to improve the health of youth with SCD, the 
intervention may be transferable to underserved youth with other chronic conditions. Further, this research is 
consistent with NINR’s strategic theme of “Self-Management: Improving Quality of Life for Individuals with 
Chronic Illness,”32 as well as the U.S. Healthy People 2020 goals of optimizing health across the lifespan and 
reducing health disparities33 for SCD and other conditions.  
 

 
RESEARCH STRATEGY 
A. SIGNIFICANCE This proposal directly responds to PA-14-029, “Chronic Condition Self-Management in 
Children and Adolescents.  The proposed multi-site randomized intervention trial is the next logical step from 
our successful feasibility trial (R21NR013745). The trial proposed here will test a replicable and scalable model 
for self-managing HU adherence in SCD to decrease disease morbidity and improve QOL. It could also be 
applied to other chronic conditions affecting underserved youth to address health disparities. Specifically:  
1. Poor medication adherence is a widespread challenge to optimizing health outcomes in chronic 
disease,34 rendering treatments less beneficial or even ineffective. Adherence problems are especially 
pronounced in underserved communities,29,30 adding to existing health disparities, increased health cost 
expenditures34,35 and decreased QOL10,36 This problem is common among youth with chronic illness, especially 
those with social, economic, linguistic and cultural barriers.16-18,20 Mismatches between providers and 
communities served are known risk factors for reduced adherence.20,37,38  Barriers to adherence include 
incomplete understanding of disease and benefits to medication use,11,19,39 access to medication22 and poor 
family adaptation to chronic illness.40 Adolescents with chronic medical conditions have especially high rates of 
poor adherence,24,26,41 especially those from under-resourced communities.41 Moreover, problems with self-
management during adolescence interferes with successful transition to young adulthood.40,42  
2. SCD is a major chronic multi-organ illness, affecting approximately 100,000 African American, 
Hispanic and other traditionally underserved communities in the U.S.1,7,43 SCD frequently affects 
underserved groups in the U.S.: 1:365 of African-American births and 1:16,300 of Hispanic-American births.1 
SCD is associated with high medical expenditures,44 early mortality, poor QOL and low rates of high school 
completion.4 Reflecting the importance of SCD to population health and reducing health disparities the federal 
Healthy People 2020 (HP 2020) program of goals for national health-promotion and disease prevention 
includes target goals for SCD.45 
3. Youth and young adults with SCD derive considerable health benefit from HU treatment,8,9,46 but poor 
adherence common,10-14,39 often reflecting poor self-management.39 HU benefits include reduced 
symptoms,7,47 health care expenditures10 and improved health QOL for the common sickle subtypes (HbSS 
and HbS-B0 thalassemia).48 Increased well-being often begins within the first months of HU,8 along with 
increased HbF levels. Optimum therapeutic effect is reached at maximum HbF response, which we refer to as 
“Personal best HbF levels”.15 Rarely is HU therapy ineffective in childhood, and is usually attributable to poor 
adherence.8,11,46 Young adults with SCD utilize health care at the highest levels of all age groups,3 including 
hospitalization and re-admission, and have high rates of poor adherence.10-15 Adult HU use is associated with 
improved outcomes49,50 and longevity,51,52 In total, these findings demonstrate the impact of HU across the 
lifespan, underscoring the imperative of establishing self-management of HU during childhood and 
adolescence. Consistent with NINR’s strategic theme of “Self-Management Improving Quality of Life for 
Individuals with Chronic Illness,” HP 2020 public health goals for SCD include the increased use of disease-
modifying therapies, of which HU is the most widely available effective treatment.7,47  
4. If demonstrated as efficacious, our HABIT intervention could be adapted to address poor medication 
adherence across other chronic pediatric conditions in underserved communities.  Our approach built 
upon Columbia’s local pediatric asthma study for underserved communities in Washington Heights and 
Harlem.53 CHW-based approaches are recommended to improve treatment outcomes for chronic pediatric 
conditions in underserved communities,54 and need successful models for implementation.  
 
B. INNOVATION. To develop a self-managed adherence habit23 for HU for youth with SCD, the proposed 
multi-site randomized HABIT trial will continue to employ several innovative aspects: 
1. Individualized Personal Best HbF target. No standard previously existed to assess HU 
adherence9,11,13,39,55 We have used and validated the highest historical HU-induced HbF as an innovative 
minimum target for an individualized Personal Best self-management goal.15,31 Long-term pediatric clinical HU 
trials demonstrated stable HbF levels over time.56-58 The personalized biomarker of Personal best HbF adds to 
other adherence measures employed and serves as a customized motivational aid. In the HABIT feasibility 
trial, coaching by CHWs on the historical Personal best HbF helped create a concrete attainable goal and was 
useful and acceptable to youth-parent dyad participants. We validated the utility of Personal best as a 
biomarker for tracking adherence in a retrospective sample of 75 youth on HU therapy15 (see Preliminary 
studies C2). 
2. Focus on underserved parent-youth dyads and developmentally appropriate delegation of 
responsibility for adherence. Chronic disease management often deteriorates during adolescence as youth 
assume greater self-management responsibility.20,59-62 Shared responsibility in youth-parent partnerships for 
self-management supports adolescents by a gradual transition to self-management.41,63-65 To our knowledge, 

the HABIT trial is the only CHW intervention to engage youth-parent dyads.  
3. Community Health Worker (CHW) support augmented by tailored text messaging. Our approach 
combines two successful research strategies for a novel multi-component approach for improved cue-based 
medication adherence.  Culturally aligned CHWs are an accepted mode of by community-based support for 
improving health in underserved communities.53,66-68 CHWs share responsibility for patient education, support 
and social services with clinical staff, and have been successful in engaging and sustaining adherence among 
adolescents. CHWs are highly effective at promoting adherence to chronic disease management regimens 
through regular, structured interactions.53 Currently, CHWs are being tested a multi-state, federally funded 
program to improve access to care for adults with SCD (LOS Banks). In the HABIT feasibility trial, CHWs 
established a trusting relationship with families and focused on helping the youth-parent dyad work together to 
address their particular barriers to medication adherence.  
    Texting health messages is effective for professional-to-parent short-term reminders,69 and are widely 
acceptable and effective for parents and adolescents.69,70 Text-based reminders to improve adherence in 
chronic pediatric illnesses may improve a biomarker but have not documented changes in health status or 
sustainability.71 Other types of electronic communication were less popular in our community for connecting 
youth and their parents.72 During the feasibility study, HABIT dyads worked collaboratively with the CHWs to 
personalize automated, cue-based text messaging to reinforce the HU habit. This approach builds on work 
demonstrating the importance of tailored communication messages.70,73 To our knowledge, this combined 
intervention has not previously been studied for improving medication adherence.  
 
C. RESEARCH STRATEGY  
1. Scientific Premise and Overall Strategy. Poor medication adherence is highly prevalent among children24 
and in adults74 with chronic health conditions. Poor adherence poses considerable risk for exacerbating health 
burden, cost and health disparities. Rigorous multi-level tracking of treatment adherence and its impact 
includes health care utilization, treatment success rates, family functioning and school/work missed, bioassays 
and symptoms.75 For SCD, widespread poor adherence for therapeutic HU for SCD has been documented by 
pharmacy refill databases10,13,76 and by reduction from peak HbF levels,13,15 the most sensitive biomarker for 
dose-dependent HU use. Systematic reviews and meta-analyses of randomized trials to improve adherence 
among youth with chronic illness support the importance of multi-modal approaches,77,78 some of which include 
community-based support.53 Trials to improve HU adherence are limited, and to date have focused on 
immediate outcomes rather than broader patient-reported outcomes, and have not used strategies for 
developing longer-term self-management71,79,80 that are sensitive to socio-cultural patient and family needs. 
Using individualized biomarker and pharmacy data, we propose a rigorously designed and implemented multi-
site randomized controlled trial to test the efficacy and sustainability of the intervention.  
 
2. Preliminary Studies. Our multidisciplinary team has complementary expertise, which ensures our ability to 
fulfill study goals. The studies that directly inform the scientific premise of this application are described below. 
    a. Expertise of the Inter-disciplinary Research Team: The majority of the research team (Smaldone, 
Green, Jia, Findley, Manwani) and consultants (Matos, Stennett) collaborated on our successful HABIT 2-
site feasibility trial. Bruzzese, with extensive experience in developing evidence-based asthma interventions to 
youth and their caregivers in school settings,81-84 and Stockwell, nationally recognized for her work in text 
messaging interventions to improve pediatric vaccination,69,70,85 bring their expertise to the research team. Our 
new site PIs Smith-Whitely, and Aygun are experienced in conducting clinical research trials, community 
based outreach, patient/family support and assessing patient-oriented outcomes.24,86-88  
 
Table 1. Study Team and Relevant Expertise   Co-I = Co-investigator 
       
 
Role 
Discipline 
SCD 
Self-
mgmt 
Adolesc 
Transition 
Community  
Intervention 
Technology  
in Health 
Clinical 
Trials 
Qual. 
Analysis  
Green 
PIs 
Pediatric Sickle Cell 
+ 
+ 
 
+ 
+ 
+ 
 
Smaldone 
PIs 
Nursing, Pediatrics 
 
+ 
+ 
+ 
+ 
+ 
+ 
Bruzzese 
Co-I 
Psychology 
 
+ 
+ 
+ 
 
+ 
 
Jia 
Co-I 
Biostatistics 
 
 
 
 
 
+ 
 
Findley 
        Co-I 
Public health 
 
+ 
 
+ 
 
+ 
+ 
Stockwell 
Co-I 
eHealth, texting  
 
 
 
 
+ 
+ 
 
Smith-
Whitely 
Site PI 
Pediatric Sickle Cell 
+ 
 
 
+ 
 
+ 
 
Aygun 
Site PI 
Pediatric Sickle Cell 
+ 
 
 
 
 
+ 
 
Manwani 
Site PI 
Pediatric Sickle Cell 
+ 
 
 
+ 
 
+ 
 

Matos 
Consultant 
CHW training  
 
 
 
+ 
 
 
 
Stennett 
Consultant 
Community services 
 
 
 
+ 
 
 
 
     b. HABIT feasibility trial: This study (R21NR013745) tested the feasibility and acceptability of the 6-month 
intervention to improve adherence to HU therapy in a sample of youth-parent dyads and estimated effect 
size31. The intervention was highly structured to assure fidelity while also tailored for individual youth-parent 
dyad needs. During months 1- 6, CHWs had monthly face-to-face interactions at the subject’s home or other 
location where privacy was assured. CHWs also met dyads at one clinic visit. To support relationship building, 
additional contact between dyad members and CHWs was maintained, as needed, by phone or text message 
by dyad member preference. CHWs communicated HbF results to the dyad soon after each test, discussed 
challenges to reducing barriers to HU adherence, and progress made to achieve Personal Best HbF. The 
structured assessment for each CHW visit is found in Appendix 6.  
    Tailored interactive text message reminders were collaboratively developed with each dyad member to 
support linking a daily cue to form a HU adherence behavior. This was initiated in month 3 to allow time for 
establishing the relationship with CHWs. Subjects lacking a mobile phone or sufficient cell phone plan were 
provided a simple cell phone or were compensated to upgrade plans to accommodate texts. Text messages 
were programmed to appear as sent by the CHW. Texts sent and received were tracked by the MIR3 texting 
system (Appendix 7).  
    Of 74 youth screened at 2 study sites, 48 met all inclusion/exclusion criteria and 28 dyads (58% acceptance) 
participated in the study. Subject attrition was 10.7%. Reasons for dyad attrition were incarceration, illicit drug 
activity (1 youth each) and burdensome study procedures (1 parent).  On average, youth were 14.3±2.6 years, 
43% female and 50% Hispanic. The majority of parents were single and/or separated from a spouse, had a 
high school education or less, and were employed full or part time. Spanish language surveys were used by 
42% of parents and 25% of youth subjects. The 2:1 enrollment scheme allowed for more feedback about the 
HABIT intervention.  
 
Feasibility and acceptability. Monthly CHW visits were feasible, although more frequent visits were not. Text 
messages were delivered as planned, once the logistical barrier of a blocked phone number was addressed.  
    The majority of parents and youth reported that they found meeting time with the CHW convenient, found 
the study’s educational materials helpful, and learned new information about SCD and HU. Intervention 
subjects reported that they felt the CHWs valued their opinion, were easy to talk to about their disease, and 
helped the dyad to improve their collaboration in managing SCD.  Subjects did not find the text messaging 
burdensome. The majority of parents (81.3%) and youth (75.1%) reported that linking the text message to the 
time of an activity made it easier to remember to take HU. When asked what they liked about working with the 
CHWs, a dyad stated “it seemed like family talking to everyone” (parent) and “it gave me a better mindset” 
(youth). Of 18 dyads who participated in the intervention, 10 (56%) required referrals made by CHWs. The 
most frequent referrals were for mental health services (n=5) and housing (n=5). CHWs met with nearly all of 
the dyads at their home; visits lasted 60-90 minutes. CHW visits consisted of conversations with both dyad 
members present, and dyads reported making progress in working together as a team. CHWs felt that a 
relationship was established with the majority (68%) of parents at the first visit, with most youth (81%) by the 
second visit and with all by the third visit.  
 
Primary outcome: improved HU adherence. At baseline, decrease of ≥20% from Personal Best HbF 
(Personal best) was higher in the control group compared to the intervention group (-42.6±21.3 vs -18.1±23.6). 
Controlling for study month the intervention group progressed to Personal best by 2.3% per month during 
months 0 to 4 (p=0.31). Some subjects in the invention group even exceeded their Personal Best goal, likely 
due to previously inadequate HU adherence. We used improvement toward Personal Best HbF as the basis for 
the power analysis of the proposed multi-site trial. Results were similar when we measured adherence by 
Proportion of Days covered by medication (PDC) using pharmacy refill data. The intervention group improved 
PDC from 64.6% (year pre-enrollment) to 79.4% at month 6, an increase of 14.8%. In contrast, the control 
group had a smaller change of 6.5% (79.4% pre-enrollment to 85.9% at month 6). 
 
Secondary outcomes: QOL and dyad concordance regarding self-management responsibility. From 0-6 
months, both generic and disease specific QOL improved for intervention youth (generic +6.3±12.6, p=0.01; 
disease specific 6.1±17.3, p=0.33) but not for controls (-2.4±9.1, p=0.57; -1.2±17.5, p=1.0). Controlling for 
month and group assignment, youth in the intervention group improved generic quality of life scores by 1.6 
points/month during months 0 to 6 (p=0.02). From enrollment to 3 months, dyad self-management 
concordance improved for intervention dyads (+1.3±2.1, p=0.03) but not controls (0.2±1.6, p=0.80).  
 

Value of booster session during the sustainability phase of proposed study. Parents (9 of 18) who 
participated in the intervention group during our HABIT feasibility trial were interviewed by telephone regarding 
their opinion of the value of an additional “booster” visit by the CHW. All felt that the extra CHW visit would be 
well accepted. The majority (89%) identified the 8 month visit as the best timing for the visit with the preferred 
location either at home (78%) or clinic (89%). All stated that weekly phone calls with CHWs would be accepted 
by parents but were not sure about weekly contact with youth.  
 
   c. Larger decline from Personal Best HbF is associated with higher urgent hospital use. To validate 
the concept of Personal best as a measure of HU adherence, we conducted a retrospective review of 75 youth 
ages 10-18 years with SCD prescribed HU at the two centers which participated in our HABIT feasibility trial.15 
HbF was examined pre-HU initiation, at Personal Best (HbF at maximum HU dose), and recent assessment. 
Decrease from Personal best HbF of ≥20% at recent assessment was considered a marker of suboptimal HU 
adherence. In contrast, a decrease of <20% was considered stable. In all, 70% of youth (n=53) met criterion for 
suboptimal adherence with average 
decrease from Personal Best HbF 
40.1±17.5% significantly higher 
compared to 11.7±5.3% in the stable 
group, p<0.001). Those with greater 
decline from Personal Best HbF differed 
from those with more stable HbF in terms 
of longer time to achieve Personal Best 
(p=0.01), higher HU dose at Personal 
Best (p=0.02) and higher recent HU dose 
(p=0.03). Resource use was measured 
over two 1-year periods: at Personal Best 
HbF (6 months pre to post Personal 
Best) and at recent HbF assessment (6 
months pre to post assessment). 
Comparing the periods for each group, 
urgent hospital visits and total hospital 
length of stay (LOS) (Figure 1) remained 
stable at recent assessment for youth with low decline from Personal Best (hospital use -0.05; p=0.52; -0.6; 
p=0.48). However, both increased for youth with larger decline from Personal Best (hospital use +1.2; p=0.01; 
LOS +5.2, p=0.001). A sensitivity analysis, conducted using cutoffs of 25% and 15%, tested the robustness of 
study findings and yielded similar results. These data support Aim 3 of the proposed study. 
 
   d. Translation and linguistic validation of PedsQL SCD module. The PedsQL Sickle Cell disease 
module89 became available to researchers in 2013. Due to its alignment with HABIT outcomes, we added it 
into the battery of survey instruments used in our feasibility study. The instrument was only available in 
English. Assisted by a PhD student at Columbia’s School of Nursing, the 8-12 year and 13-18 year versions of 
the instrument underwent a forward and backward translation process. Twenty subjects (10 parents, 10 youth 
with SCD, half in each age group) participated in the final phase of validation. Each subject first completed the 
translated questionnaire and then participated in a cognitive interview to determine whether questionnaire 
directions, questions and response choices were clear, relevant, appropriate, and easily understood. The 
translated survey was well received and required no changes. The long term goal is to make the instrument 
available to researchers to allow participation of Spanish speaking youth with SCD and their parents. A report 
of the process of translation and a summary of the cognitive interviews was submitted to MAPI Institute. 
 
Proposed HABIT Intervention Study: 
3. Theoretical Frameworks. The Self and Family Management Framework90 guides the study design for Aims 
1-3. Designed to better understand and improve self- and family self-management of chronic conditions, the 
framework addresses key youth and family risk and protective factors for youth and family. These factors 
include health status, individual and family factors, environmental context and developmental aspects. 
Recently updated, the revised framework91 highlights processes such as activation of resources to promote 
self-management of chronic illness and differentiates proximal from distal outcomes. In this study we examine 
the efficacy and sustainability of a community intervention employing CHWs (process) on proximal (adherence 
behaviors and symptom management) and distal (quality of life, self-management responsibility concordance 
and health status) outcomes. Subjects ages 10-18 years are targeted for the HABIT intervention because 
transition of responsibility for self-management occurs throughout this time59,92,93. The PRECEDE portion of the 
PRECEDE-PROCEED Model of health program planning and evaluation38 guides the qualitative interviews 

and analysis of Aim 4. The model has been widely used in evaluation of health interventions such as physical 
activity94 and obesity prevention.95,96 In the proposed study, we use PRECEDE to gain better understanding of 
the effect of the HABIT intervention and its sustainability from the perspectives of the dyads who received the 
intervention and the CHWs who delivered it. These perspectives will provide context for interpretation of the 
quantitative findings and potential for broader dissemination of the HABIT intervention. 
 
4. Setting. Parent youth dyads will be recruited from 4 pediatric Sickle Cell Centers (Columbia University 
Medical Center, NY, NY; Montefiore Hospital, Bronx, NY; Cohen Children’s Medical Center at Northwell 
Health, Queens, NY; Children’s Hospital of Philadelphia, Philadelphia, PA). Each provides comprehensive 
multi-disciplinary care to youth with SCD. Considerable diversity in patient population exists within and among 
sites, including African American, African, West Indian and Latino families, as well as geographic and 
urban/rural location diversity. PIs at all participating sites have strong histories of successful recruiting and 
retaining of pediatric SCD patients for randomized trials,88,97-99 despite potential barriers to trial enrollment.100-
104 While the volume of patients at each center varies (see Resources), we are confident that each site has 
sufficient youth who will both meet eligibility criteria and be interested in study participation (see Enrollment 
Feasibility) and will be successful in hiring experienced CHWs to deliver the intervention (see C6).  While 
Cohen-Northwell has not worked directly with CHWs, they are experienced in working with the Sickle Cell-
Thalassemia Patient Network, New York City’s most established SCD patient group. Each site has wireless 
Internet in their clinic to allow use of iPad technology for direct entry of survey data into the HABIT RedCap 
database. All study visits will take place in the SCD outpatient clinic setting.  
 
5. Study Participants. To achieve Aims 1-3, a total of 104 youth-parent dyads meeting eligibility criteria 
(Table 2) will be recruited. Clinic rosters of youth ages 10-18 years and on HU therapy will be assessed for 
eligibility. Potentially eligible patients will be assessed for large decrease (≥20%) from Personal best HbF over 
the preceding 12 months. Those passing the initial screening will be telephoned for invitation to study 
participation. Of those interested, eligible dyads will be confirmed for full eligibility at their clinic visit. Those who 
meet all eligibility criteria will be offered enrollment until full enrollment is reached. Numbers and reasons for 
declining participation will be tracked at each site and cumulatively.  
 
Table 2. Subject Eligibility and Exclusion Criteria  
INCLUSION CRITERIA - YOUTH 
EXCLUSION CRITERIA - YOUTH 
1. Sickle type HbSS or HbS-B0 thalassemia 
2. Age 10 through18 years (inclusive) 
3. Currently prescribed HU ≥18 months (for identifying historical 
Personal best HbF) 
4. Current HU dose is within 5% of dose at Personal Best HbF. 
For youth whose dose at Personal Best was ≥30mg/kg and 
whose current dose does not meet the 5% entry criterion, the 
dose of HU may be increased based on youth’s current body 
weight not to exceed 30mg/kg. If subject meets all other 
entry criterion, subject may be recruited 3 months after dose 
adjustment  
5. Pre-enrollment HbF ≥15% below historical Personal best, 
based on mean of ≥2 HbF assessments over preceding 12 
months  
6. Youth able to speak/read English or Spanish  
                                                                     
INCLUSION CRITERIA - PARENT 
1. Youth not prescribed HU  
2. <3 HbF assessments over past 12 months 
3. Transfusion within 3 months preceding enrollment 
4. Final screen HbF (visit 0) of ≤15% decrease below 
Personal best HbF 
5. Sexually active female ≥10 years and not using reliable 
contraception (due to HU teratogenic risk) 
6. Pregnancy 
7. Cognitive impairment (>2 levels below expected grade) 
8. Youth not residing with parent/legal guardian  
9. Sibling of a youth enrolled in this study 
1. Parent/guardian speaks/reads English or Spanish 
2. Parent/ legal guardian willing to participate 
 
EXCLUSION CRITERIA – PARENT 
3. Family expects to reside in community for ≥ 1.5 years 
1. Parent/legal guardian does not reside with youth          
   
For Aim 4, we will recruit two independent purposive samples of approximately 10 youth-parent dyads 
randomized to the HABIT intervention at each of 2 time points during their study experience: 6 months 
(perceived intervention impact) and 12 months (sustainability). The sample will represent dyads who make 
good progress to Personal Best HbF as well as those who continue to struggle with HU adherence.  
 
6. Study Implementation Procedures 
 
Randomization. A 1:1 randomization plan will be generated using computerized random number generator. A 
randomization plan will be generated for each site to achieve balanced randomization and will be maintained 
centrally at Columbia University Medical Center. Assignments to group will be placed in sequentially numbered 

sealed envelopes stratified by site. Following subject consent and final screening, the site coordinator will 
contact Columbia PI for dyad assignment and study ID number.   
 
Recruitment and retention 
    Subject enrollment. Prior to study enrollment, parent/legal guardian consent and youth assent will be 
obtained by site coordinators for: study participation, release of pharmacy refill information for the year prior to 
study entry and for the duration of study participation, and (intervention arm only) for communication of HbF 
results and urgent clinical events to the CHW by study staff. A final screening will ensure that current HbF is 
consistent with levels over the past year. This screening will require the month 0 HbF level to be ≥15% below 
Personal best HbF (exclusion criterion 4). Randomization will await determination of this final eligibility 
criterion.  
    Enrollment feasibility. Full enrollment of 104 dyads (52 per study group) is expected based on excess 
number of eligible subjects (Table 3) and our HABIT enrollment experience during our feasibility trial. Three 
sites (CHOP, Cohen-Northwell and Montefiore) have capacity to enroll additional subjects in case of 
insufficient enrollment elsewhere.  Despite compelling evidence of the value of HU therapy for youth with SCD, 
research has not translated into universal uptake.7,19 Therefore trials like HABIT require multiple sites. Table 3 
provides detail regarding enrollment expectations from each site using data from our 2-site retrospective 
analysis15 to estimate the proportion of subjects who will meet the criterion of ±20% greater decrease from 
Personal best (i.e., 70%), and data from our feasibility trial to estimate the proportion of eligible children 
expected to consent (i.e., 58% of eligible subjects). With these sites we will achieve a sample size of 104 
dyads, sufficiently powered to achieve the aims, while allowing for 20% subject attrition and/or receipt of blood 
transfusions (that alter HbF).105  Bi-monthly study visits is within the range of usual care frequency for patients 
on HU at each site. 
 
Table 3. Estimation of target recruitment from each study site 
Site  
# 10-18 yrs 
on HU 
# ≥20% below 
Personal best 
# Estimated to 
consent 
Target enrollment 
CHW or related experience 
Columbia 
48 
33 
19 
16 
HABIT study 
Montefiore 
69 
48 
28 
24 
HABIT study 
Cohen-Northwell 
90 
63 
36 
24 
No 
CHOP 
200 
140 
81 
40 
SCDAA 
TOTAL  
461 
322 
186 
104 
 
CHOP- Children’s Hospital of Philadelphia; SCDAA –Sickle Cell Disease Association of America through their federally funded CHW 
program  
 
    Retention We expect high dyad retention based on low attrition (10.7%) during our HABIT feasibility trial; 
patients’ long-term care at each SCD center; excellent enrollment and retention in previous SCD clinical trials 
under the PIs at each site; coordination of study visits with regular appointments; acceptability of text 
messaging for health interventions; and subject incentives weighted to study completion for extra time 
completing questionnaires (see Human Subjects). Additionally, our planned 20% over-enrollment provides a 
cushion for subject attrition. 
 
Study Groups Youth-parent dyads will be randomized to the HABIT intervention or the control group. They will 
be blinded to specific study hypotheses, even though they cannot be blinded to the assigned group. Both 
groups will have bi-monthly clinic visits over the 12 month study. In addition, intervention subjects will have 
visits with the CHWs as detailed below. 
Data regarding laboratory assessment, hydroxyurea dosing and urgent hospital use will be collected at each 
visit by the study coordinator or his/her designee.  
Control Group. Dyads 
randomized to the control group 
will continue usual bi-monthly 
clinic-based care, including 
monitoring and review of HbF 
levels, and similar SCD team staff. 
They will receive the same 
educational materials (Appendix 
5), complete the same 
questionnaires (Appendices 3, 4) 
and laboratory assessments as 
the Intervention group. They will 

not receive CHW support or text messages.   
    Intervention group. The feasibility trial is now replicated in the proposed intervention trial (Figure 2) with 
the following additions: a) Dyad coaching on developing additional social support to enhance sustainability; b) 
More study sites (5 versus 2) and subjects (28 versus 104 dyads); and c) 6-month sustainability phase.     
CHW training and supervision are described below. The structured assessment for each CHW visit is found in 
Appendix 6. 
 
MONTHS 1-2: Month 1: One CHW visit at the home or other private location will initiate relationships between 
the CHW and youth-parent, individually and as a dyad to assess social, educational and self-management 
needs and identify barriers to HU adherence. CHWs will help dyads prioritize adherence barriers, address 
knowledge gaps about HU benefits/risks, and help dyads establish a shared plan for attaining HU adherence 
goals. Referrals for social services or other needs such as job training will be made to either the site’s social 
services, community-based organization and/or other social service agencies in the community. Results of 
each bimonthly HbF testing months 0 through 8 and progress to personal best will be reviewed with the dyad 
by the CHW. 
   Month 2: CHW and dyad will jointly attend a SCD clinic visit to strengthen linkage with the SCD clinical 
service, and aid the dyad in reviewing plans to reduce adherence barriers. In addition, CHWs will meet with the 
dyad at home to focus on addressing adherence barriers, HU education and self-management strategies using 
a problem-solving approach. Additional service referrals will be made, as needed. Goals for youth self-
management responsibility will be mutually agreed upon by the dyad, based on his/her age and capabilities, 
and regularly reviewed by the CHW. 
MONTHS 3-4: CHWs will continue to support dyads on their roles and steps toward coordinated self-
management, facilitate problem-solving to address barriers to a daily HU habit, and identify additional sources 
of personalized support for each dyad member (e.g. a relative or neighbor). Interim goals and progress toward 
goal achievement will be reviewed at each visit. Self-management issues will be addressed, depending on 
youth’s age and developmental stage.  
    Month 3: The established CHW relationship will facilitate the CHW in coaching each dyad member to 
develop a text message reminder about taking HU: identify a daily cue-based habit to link to HU use, 
personalize text language, time of day and options of responses. Texts developed by dyads in the feasibility 
trial will serve as examples to help dyads develop a text message tailored to language, daily habit on which the 
cue is based and time of day preferences. CHW will clarify that messages are not their direct communication, 
but that they will receive timely information about texts from study staff. Contact with CHWs, if desired, can be 
made directly with CHWs via cell phone or text message. 
    Month 4: Begin daily text message reminders to parents and youth. Automated personalized text messages, 
delivered through MIR3 Notification solution, are intended to augment habit-forming behavior and extend on-
going support for a cue-based HU habit. The MIR3 system was used successfully during our HABIT feasibility 
trial and has been useful for Columbia faculty to automate communication with community-based research 
subjects69,70,106,107.  
Text messages will link HU reminders to the cue determined by each CHW-dyad, and will encourage a 
response such as “1” (taken) or “2” (not taken) or “3” (will take later), along with an option for sending free text, 
such as how they are feeling, problems with the medication, etc. Study staff will review text responses 2 times 
weekly and share them with the CHWs.   
MONTHS 5-6: Continued CHW focus on self-management, adherence and coaching to personal best HbF. 
Monthly CHW visits will continue. Using dyad text message response data from MIR3, weekly phone contact 
will be initiated in month 5 and continued through month 6 to provide positive reinforcement of HU adherence 
or to problem solve regarding why adherence has been a problem. To avoid habituation to text messages, the 
frequency of text messages will be negotiated based on preference of each dyad member at the end of month 
5.  
MONTHS 7-12: During the sustainability phase one CHW visit during month 9 will be scheduled to “boost”108 the 
effect of the intervention. This visit will be scheduled at the home or clinic, based on dyad preference. CHW 
focus will be limited to providing support by addressing questions or concerns that the dyad may have about 
issues related to adherence. During the sustainability phase, subjects will continue usual bi-monthly clinic 
visits, HbF and other laboratory assessment, and complete study questionnaires. We will track all dyad contact 
with the CHW during the sustainability phase. 
 
Due to the COVID-19 pandemic and its implications for mental health distress, maladaptive behaviors (e.g. 
drinking, domestic violence), and food insecurity particularly in vulnerable populations, we will survey former 
and current parents and youth HABIT study participants using survey questions from the COVID-19 and 
mental health measurement working group at Johns Hopkins Bloomberg School of Public Health.  All items are 
taken from valid survey instruments such as the CES-D (depression), GAD-7 (anxiety). We added 2 additional 

items regarding food insecurity from the American Academy of Pediatrics recommended Hunger Vital Sign. 
The parent survey contains 18 items and the youth survey contains 15 items (an English and Spanish version 
of the parent and youth surveys are attached). Both surveys were translated to Spanish by our study team.  
 
We propose to distribute the survey by either email or cell phone message that will provide a unique link to a 
REDCap survey. Using a script, the research coordinator at each site will contact both former and current 
study dyads of the HABIT Efficacy trial to describe the survey, participation is voluntary and that if a question 
makes them uncomfortable, they do not need to answer it. Current HABIT dyads will be contacted via 
telephone using a script; former HABIT dyads will be reconsented for participation by telephone using an 
information sheet. Participants will respond to the survey using their language of choice (English or Spanish). 
We propose to distribute the survey using the same platform, REDCap, as all other surveys administered as 
part of the HABIT study as soon as IRB approvals are obtained at each of the 4 study sites and again 2-4 
months later to see the effect over time. Because of the sensitive nature of survey questions, research 
coordinator at each study site will monitor all survey responses as soon as possible and refer any "red flag" 
issues (e.g. domestic violence) to the social worker at the respective clinical site so that the patient may be 
referred for mental health services. 
 
Qualitative Interviews with Dyad members. A purposive sample of parent-youth dyads from each clinical 
site will participate in individual interviews at 2 time points: after completing the 6-month study visit and at study 
completion (12 months). Interviews will be conducted by the coordinator at each site either face to face at the 
clinic or by telephone using uniform interview guides informed by the predisposing, enabling, and reinforcing 
constructs in Evaluate (PRECEDE) portion of the PRECEDE-PROCEED Model of health program planning 
and evaluation.38 Interviews for parents and youth will be conducted separately and each is expected to last 
approximately 20-30 minutes. Subjects will be compensated $20 for their time. The interview guide for the 6 
month interview will be directed to intervention impact. Interview guide questions for the 12 month interview will 
be geared toward the sustainability of the habit from the perspective of youth and parents. All interviews will be 
conducted in English, audiotaped, and transcribed for analysis. Based on clinic demographics at each site, 
most subjects will be fluent in English. 
    Sample questions will include:  
• Tell me about the habit that you (your child) developed to make it easier to remember to take hydroxyurea 
every day? (reinforcing factor) 
•  What are some of the ways that you think your (your child’s) health will improve through maintaining a 
hydroxyurea habit? (reinforcing factor) 
•  What do you perceive as barriers to maintaining a hydroxyurea habit? (predisposing factor); What are your 
ideas for how to maintain the habit that you (your child) have established? (enabling factor). 
 
    Focus groups with Community Health Workers: We will conduct 2 focus groups with all of the study 
CHWs at two time points: study mid-point (18 months) and end-point (36 months). Both focus groups will be 
conducted in English by webinar. CHWs will have become familiar with virtual meetings during monthly group 
supervision meetings as described below. Focus groups will be conducted in English, last approximately 60 
minutes and will be led by Mr. Matos. The focus group interview guide questions will focus on the CHWs 
experiences with the dyads regarding the predisposing, enabling and reinforcing factors and their relationship 
to intervention impact and sustainability. Focus groups will be audiotaped and transcribed for analysis.      
 
Intervention Training and Supervision 
Training and Supervision.  A study orientation meeting of all site PIs and coordinators will be held at 
Columbia early in year 1 prior to subject enrollment. At that meeting, Green and Smaldone will present the 
study’s main goals and strategies, including lessons learned from our feasibility trial, review the study protocol 
and address issues at any of the sites.  
    CHW Training. Two CHWs with prior CHW experience will be hired for the HABIT study at each site. The 
Co-PIs and site PIs will discuss leading candidates and will review the vetting process to ensure quality of 
CHWs and their prior training. Following hiring, CHWs from all sites will participate in a 4-day training session 
at Columbia led by Matos66 (see LOS). Training will use the structured training curriculum from the HABIT 
feasibility study.31  The first 2 days will serve as a “refresher” regarding CHW core concepts such as role and 
responsibility, engagement with families, and role boundaries. Days 3 and 4 of training will provide project-
specific training, to include goals, rationale and approach by the HABIT study, schedule and goal of each CHW 
visit, information about SCD and HU (Smaldone and Green with Matos). Project specific skills, e.g., 
establishing relationships with dyads, helping dyads to work together to address barriers to HU and identify 
established daily patterns on which to build a HU habit, communication with the medical team will be 

addressed through discussion and role playing. Stennett will discuss the importance of community support 
and resources for families faced with chronic illness (see LOS). Bruzzese will work with the group regarding 
motivational interviewing skills and self-management expectations for youth at varying age levels. The added 
benefit of group training is for the CHWs form a group allied for sharing experiences during supervision 
sessions over the course of the project. For any “red flag” issues (truancy, depression, drug use, potential 
violence), CHWs will be directed to immediately inform their site coordinator for referral to the clinic’s social 
services. 
    Supervision. CHWs will have weekly ongoing supervision sessions to ensure high quality support to 
families, study fidelity, CHW progress with dyads and challenges to adherence, and detection of any barriers to 
progress towards an HU habit. Supervision schedule will include: a) bi-weekly site meetings with their 
coordinator to problem-solve for logistics of visits and the relationships with dyads, discuss on-going barriers to 
progress and reinforce the communication of HbF levels to dyads. b) Monthly site meetings jointly with their PI 
and coordinator will review additional study information and other social or medical issues; c) Matos (with 
Smaldone and Green) will lead monthly CHW group supervision sessions delivered via webinar for all CHWs 
to reinforce training components and ongoing case supervision; and d) At quarterly sessions, additional input 
to the CHWs on community-based intervention will be provided by Stennett. CHWs will share their 
experiences in delivering the intervention and will learn from the collective experiences.  
    If youth-parent dyads display unresolved conflict regarding self-management or other youth-parent 
relationship issues, Matos and Bruzzese will guide the approach of the staff and CHWs. Each site PI will meet 
with their respective CHWs a minimum of once per month with site coordinators the remaining weeks for CHW 
caseload updates, communicate with CHWs regarding subject HbF progress, information that may trigger 
clinical or social worker contact (e.g. turmoil in the home, missed school due to recurring disease symptoms or 
truancy), and to review all CHW visit forms and automated text messaging reports.  
 
Treatment Fidelity will be assured through a structured intervention protocol (Figure 2 and Appendix 6), 
ongoing CHW supervision and monthly communication with site PIs and study coordinators. The HABIT 
operations manual contains: CHW encounter forms to structure and document the content of each scheduled 
encounter, monthly schedules and objectives to guide family discussion, key messages to promote HU 
adherence and youth-parent self-management partnership, exemplars of cues for text messaging reminders, 
and information for families on SCD and HU to be reviewed with dyads. CHW delivery of intervention and 
completed visit forms will be reviewed weekly during supervision. Feedback and guidance will be provided to 
CHWs for each dyad. Monthly conference calls will be held each for coordinators and for site PIs to oversee 
enrollment schedules, scheduling and logistics of home visits, obtaining pharmacy refill data, and study 
procedures and to problem-solving, as needed. To assure validity of HbF values, the subject’s transfusion 
history will be reviewed during each coordinator call. Levels will be discarded if the subject had been 
transfused within the preceding 90 days, per standard HU protocols.105  
 
Variables and Operational Definitions: Table 4 overviews the variables including HbF levels and standard 
blood work for clinical monitoring, their relationship within the revised Self and Family Management   
     
Table 4. Study Measurement and Tools 
Concept/Variable 
Operational Definition/ Source document 
P Y Month 
Facilitators and Barriers 
 
 
 
Health Status 
 
 
 
 
   Personal best HbF 
Highest historical HbF; Medical record 
 
• 
0 
   Pre study HbF  
Mean Preceding 12 month average of ≥3 HbF±standard deviation; 
Medical record  
 
• 
0 
   Decrease from personal 
best  
% difference between personal best and Pre HbF; Medical record 
 
• 
0 
   Past year’s urgent medical 
service use 
Hospitalization, ER visits, total hospital length of stay and 
transfusions for past 12 months: Medical record  
 
• 
0 
   Past year’s HU adherence 
Pharmacy refill (proportion of days covered) for past 12 months 
 
• 
0 
Health and HU monitoring 
 
 
 
 
   HbF 
 
 
• 
0, 2, 4, 6, 9, 12 
   CBC with reticulocyte count 
Hb, MCV, platelet and absolute retic count, WBC, ANC 
 
• 
0, 2, 4, 6, 9, 12 
   Liver and renal function tests   Total and indirect bilirubin, AST, ALT, creatinine, BUN 
 
• 
0, 6, 12 
Personal/Lifestyle 
 
 
 
  Age; Gender 
Years; Male/female; Demographic survey 
• 
• 
0 
  Race/ethnicity 
African American; Hispanic; Demographic survey 
• 
• 
0 
  Grade level (youth) 
1 through 12; Demographic survey 
 
• 
0 
  Parental education  
<high school (HS); HS graduate; college; etc. Demographic survey 
• 
 
0 
  Barriers to HU use 
25-125; higher score = more barriers; Medication Barriers scale 
• 
• 
0, 6, 12 

Proximal Outcomes 
 
 
 
Behaviors 
 
 
 
   Self-management 
responsibility 
1-50; higher score = greater responsibility; SCD Family Responsibility 
• 
• 
0, 2, 4, 6, 9, , 12 
   Personal best HbF progress 
HbF change; Medical record 
 
• 
0, 2, 4, 6, 9,  12 
   Adherence 
Progress to Personal best HbF (biomarker) 
 
• 
0, 2, 4, 6, 9, 12 
 
Pharmacy refill (proportion of days covered) Pharmacy records 
 
• 
0, 2, 4, 6, 9, 12 
   Symptoms 
Pain interference 
• 
• 
0, 2, 4, 6, 9, 12 
 
Pain intensity 
• 
• 
0, 2, 4, 6, 9,  12 
 
Fatigue 
• 
• 
0, 2, 4, 6, 9, 12 
 
Depressive symptoms 
 
• 
0. 6, 12 
 
Emotional distress - Depression 
• 
 
0. 6, 12 
Distal Outcomes 
 
 
 
 
Family 
 
 
 
 
   Parent productivity 
 
 
 
 
     Work related 
1-10; higher score = greater lost productivity; RUQ 
• 
 
0, 2, 4, 6, 9, 12 
     Non work related 
1-10; higher score = greater lost productivity; RUQ 
• 
 
0, 2, 4, 6, 9, 12 
Individual/Family Outcomes 
 
 
 
 
   Quality of life 
Generic 0-100; higher score = greater quality of life; PedsQL generic 
core scale  
• 
• 
0, 4, 9, 12 
 
Disease specific 0-100; higher score = greater quality of life; PedsQL 
Sickle Cell Disease Module 
• 
• 
0, 4, 9, 12 
   Self-management 
concordance 
Self-management areas with consensus of responsibility; 0-10 with 
higher score=better communication; SCD Family Responsibility 
• 
• 
0, 2, 4, 6, 9, 12 
   School attendance 
Less missed school (days/past 2 months); RUQ 
• 
• 
0, 2, 4, 6, 9, 12 
Health Care Use 
 
 
 
 
   Emergency room 
Number ER visits in past 2 months; RUQ; Medical record 
• 
 
0, 2, 4, 6, 9, 12 
   Hospitalization 
Hospitalizations in past 2 months; RUQ; Medical record 
• 
 
0, 2, 4, 6, 9, 12 
   Hospital length of stay (LOS) 
Total LOS in past 2 months; RUQ; Medical record 
 
 
 
   Urgent visits 
Urgent outpatient visits/past 2 months ; RUQ; Medical 
• 
 
0, 2, 4, 6, 9, 12 
Subject satisfaction 
 
 
 
 
   Participant feedback 
Evaluation survey 
• 
• 
12 
Abbreviations: HbF = Hemoglobin F; HU = Hydroxyurea; P = Parent; Y = Youth; 0 = enrollment; 2 = 2 months; 4 = 4 months; 6 = 6 
months; 9 = 9 months; 12 = 12 months; PedsQL = Pediatric Quality of Life; RUQ = Resource Use Questionnaire;  
 
framework,91 operational definitions, data sources and timing of data collection. All self-report instruments are 
found in Appendices 3 and 4. All measures piloted in the R21-funded feasibility study were valuable and will be 
used again. The exception is the Morisky scale of self-report medication adherence. This scale was found to 
be inconsistent with more objective biomarker and pharmacy refill. To address this, we have added 3 pediatric 
Patient Reported Outcomes Measurement Information System (PROMIS) measures (pain interference109, pain 
intensity and fatigue) to capture self-report of fatigue110 and impact of pain from a youth and parent 
perspective111. PROMIS measures have been validated across multiple disease types for children112, have 
been validated in youth with SCD with scores responsive to hospitalization for sickle pain and subsequent 
recovery.87 All survey data will be added directly into RedCap by the study participants with the exception of 
the demographic survey.  Since that survey contains name, address and other identifying information, parent 
subjects will complete this survey via paper.  The coordinator at each site will transcribe de-identified 
responses into RedCap.  The paper survey will be stored in a locked cabinet in the PIs office together with the 
consent and assent. 
 
    Demographic questionnaire: 29 item questionnaire obtains youth-parent demographic information, 
medication profile and12 month prior resource use.  
    Medication Barriers scales: 25 (parent) and 26 item (youth) 5 point Likert scales with established content, 
construct, and internal consistency17. Notably, the scale has established criterion validity with medication 
adherence17. Parent and adolescent scales were modified by adding 9 HU specific items19. 
    Sickle cell Family Responsibility Scale: 10 items; adapted from the Diabetes Family Responsibility 
Questionnaire (DFRQ)63; measures youth-parent perceptions of who takes responsibility for self-management 
tasks, division of responsibility65,113, dyadic agreement63,114; established internal consistency and concurrent 
validity (English, Spanish)115. DFRQ was adapted for use in asthma116, inflammatory bowel disease117, HIV59. 
    Resource Use Questionnaire: 11 items; adapted for SCD from the Resource Utilization Questionnaire for 
Type 1 diabetes (RUQ-T1DM)118 with established content and criterion validity; uses a societal perspective.  
    PedsQL Generic Core Scale: 23 item 5 point Likert scale; 2 versions for youth (ages 8-12; 13-18 years) 
with parallel parent proxy version. High internal consistency for instrument (α=0.91) and subscales (α=0.81-
0.89)119 and has been validated in youth with SCD120-123; validated in Spanish.  

    PedsQL Sickle Cell Disease Module: 43 item 5 point Likert scale; 2 versions for youth (ages 8-12; 13-18 
years) with parallel parent proxy version. High internal consistency for instrument (α=0.95) and subscales 
(α=0.69-90)89; validated in Spanish (see Preliminary Studies C2). 
    Pain Interference – Short Form: 8 item 5 point Likert scale; developed as part of the PROMIS initiative; T-
score scale with mean = 50 and standard deviation = 10109; youth and parent proxy versions; available in 
Spanish. 
    Pain Intensity – 1 item visual analogue scale; scores range from 1-10; developed as part of the PROMIS 
initiative; examines perception of intensity of pain for the past 7 days; youth and parent proxy versions; 
available in Spanish. 
    Fatigue – Short Form: 10 item 5 point Likert scale; developed as part of the PROMIS initiative; T-score 
scale with mean = 50 and standard deviation = 10110; youth and parent proxy versions; available in Spanish.  
    Depressive symptoms (youth): 8 item 5 point Likert scale; developed as part of the PROMIS initiative; T-
score scale with mean = 50 and standard deviation = 10, available in Spanish. Youth with depressive symptom 
T scores greater than 2 standard deviations above the mean will be referred for mental health counseling.  
    Emotional distress – depression: 4 item 5 point Likert scale; developed as part of the PROMIS initiative; 
T-score scale with mean = 50 and standard deviation = 10, available in Spanish. Parents with emotional 
distress T scores greater than 2 standard deviations above the mean will be referred for mental health 
conseling. 
    Evaluation survey: 26 item (for intervention group; 8 items for control group) investigator developed survey; 
5 point Likert scale to assess impact on self-management, usefulness of materials, quality of CHW interaction, 
text messaging, cue-based medication reminders, outcomes, projected long-term study impact on disease self-
management; 4 open ended items. 
    COVID-19 survey: 18 item (parent) and 15 item (youth) survey to measure mental health, maladaptive 
behaviors and food insecurity experienced by participant during the COVID-19 pandemic. All items taken from 
previously validated surveys.  
 
D Analytic Plan 
Power and sample size analysis: We estimated the statistical power to compare score changes from the 
baseline to the follow-up times (for testing both improvement and sustainability) between the intervention and 
the control groups using the mixed model described below. All power analyses were based on the mixed 
model with 2-sided test and α < 0.05. We assume that the outcome measure had a high correlation coefficient 
of 0.7 at different times and the clustering with each site was low with an intra-cluster coefficient (ICC) of 0.1. 
We also assume that this study will have 4 sites and each site has 16 to 40 subjects (total 104 subjects at the 
start of study). In each site, subjects will be 1 to 1 randomly assigned to the intervention and the control group 
with 20% attrition rate by the 12th month. For the DID analysis, we will have 83.2% power to detect a medium 
effect size of 0.6. We also estimated the statistical power to compare the trend of score changes from the 
baseline to the end of follow-up between the intervention and the control groups for outcomes that will be 
measured every 2 months from month 0 to month 12 visit. We will have 85.6% power to detect a small effect 
size of 0.25. 
 
Data analytic plan by Study Aim 
Aims 1-3:  
    Aim 1: Improve daily hydroxyurea (HU) adherence measured by two primary outcomes: biomarker 
(approach or exceed a historical Personal best HbF) and pharmacy refill (proportion of days covered).  
Hypothesis 1: Compared to the control group, dyads randomized to the intervention will improve medication 
adherence at 6 months, with sustained improvement at 12 months. 
    Aim 2: Improve quality of life and self-management responsibility measured by three secondary outcomes: 
generic and disease-specific QOL and parent/youth concordance regarding delegation of self-management 
responsibility. Hypothesis 2: Compared to the control group, dyads randomized to the intervention will report 
improved quality of life and self-management responsibility concordance at 6 months, with sustained 
improvement at 12 months. 
    Aim 3: Improve health status measured by two secondary outcomes: acute hospital use (12 month hospital 
length of stay, admissions and emergency room visits) and self-reported disease symptoms (fatigue, pain 
interference and intensity). Hypothesis 3.1: Compared to the control group, dyads randomized to the 
intervention group will demonstrate decreased acute hospital use at 6 months, with sustained improvement at 
12 months. Hypothesis 3.2: Compared to the control group, dyads randomized to the intervention group will 
report decreased disease symptoms at 6 months, with sustained improvement at 12 months. 
   COVID-19 survey - Data will be analyzed using descriptive statistics. "Red flag" responses (e.g. domestic 
violence) will be referred to clinic social worker for management. Parent and youth responses will be 
compared.  

 
Data analysis will be led by Jia. Analyses are based on intention to treat. All randomized subjects will be 
included in the analyses regardless of whether they adhered to the intervention protocol. Descriptive statistics 
will be used to profile outcome measures at each data collection point for the intervention and control groups. 
Distributions of all outcome variables will be made at the observational level instead of at the subject level. 
Medication adherence and quality of life assessments will be made at the 0, 6, and 12 month visit. Some 
outcomes (HbF, parent/youth concordance) will be assessed every 2 months from 0 to 12 month visit. We will 
compare hospital length of stay, emergency room visits, and hospitalizations during 3 time periods: 0-6 to the 
year prior, months 0-6, and months 7-12. The main analysis will be difference-in-difference (DID), comparison 
of changes in outcomes at 6 month from 0 month (improvement) and 12 month from 0 month (sustainability) 
between the intervention and the control group. We will use linear mixed model or generalized linear mixed 
model. Linear mixed models are used for most continuous outcomes (e.g. QOL score) and generalized linear 
mixed models are for categorical outcomes (e.g. whether or not a subject had an urgent outpatient visit with 
logit link function) or for outcomes with skewed distribution (e.g. length of stay with log link function). We will 
incorporate a site-specific random effect in the mixed models for controlling for clustering within each site. The 
mixed models are also used for outcomes that will be assessed every 2 months from 0 to 12 month visit to 
exam the difference in trend during the follow-up period. The mixed model is used to address the hierarchical 
data structure of multiple observations for each subject and multiple subjects in each family (i.e. youth-parent 
dyads) as well as for repeated measured data. 
 
Missing data: Attrition or other missing data (survey or invalid HbF result due to recent transfusion) will be 
addressed by a plan to: (1) Apply a mixed model to include all subjects in the analysis; (2) Conduct a sensitivity 
analysis to estimate magnitude and direction of bias by imputing missing outcomes; and (3) Ask dyads who do 
not complete follow-up interviews about their reasons why and include such information in the model to correct 
the bias.   
 
Aim 4: Qualitatively explore impact and sustainability of the intervention on developing a daily medication (HU) 
habit from the perspectives of the community health workers and youth-parent-dyads using focus group and 
individual interviews (exploratory aim).   
    Data analysis will be conducted by Smaldone124-126 and Findley37 both experienced in qualitative analysis. 
Each focus group and individual interview will be transcribed.  The research team will ensure the credibility, 
confirmability, dependability and transferability of the qualitative data. To assure credibility we will conduct peer 
debriefing and triangulate findings across data sources (focus group, individual interview, survey data), use 
member checking, sharing of data interpretation with participants for accuracy. Triangulation of findings will 
enhance confirmability of findings.  The research team will maintain an audit trail and maintain extensive field 
notes to facilitate transferability of findings. All transcripts and field notes will be analyzed using NVivoTM (QSR 
International, Victoria, Australia) software. Data will be sorted into categories by PRECEDE constructs: 
predisposing, enabling, and reinforcing to allow better understanding of the impact and sustainability potential 
of the HABIT intervention.   
 
E. Scientific Rigor: Our interdisciplinary team has an outstanding track record of rigorous study design and 
implementation, including our prior feasibility trial. Several measures will be employed to generate valid and 
generalizable knowledge and to minimize bias. These include: 1) To avoid bias in study patient demographics, 
including sex, ethnicity and any additional medical conditions, offering study enrollment to sequential eligible 
patients at each site until the site sample is filled; 2) A 5-site study across differing study settings in three 
states assures greater diversity in subjects and circumstance and greater generalizability; 3) A careful central 
process for randomization of subjects within each site to help prevent bias in study arm assignment; 4) Use of 
objective data for assessing HU adherence, including determination of HbF when not affected by transfusion33 
and obtaining pre-study and 12 month study data on medication refills (Aim 1); 5) Self-reporting outcomes to 
augment staff report on acute hospital use, in case patients receive urgent care at other institutions during the 
12-month study (Aim 4).76  
 
F. Study limitations and alternative strategies 
    Sufficient enrollment: Planned 20% over-enrollment and minimizing subject attrition will support full 
enrollment. In addition, three participating sites (Montefiore, CHOP and Cohen-Northwell) have excess 
capacity in case other sites cannot fully enroll.  
    Investigator and subject blinding: As CHWs have a major role in the intervention, blinding is not possible. 
Our procedure for allocation concealment minimizes potential bias regarding group assignment. Further, 
blinding will be maintained during the data analysis process.   

    Sample size insufficient to compare the effect of individual intervention components, CHWs and text 
messaging: Capture of dyad replies to text messages recorded by MIR3, as well as post-intervention focus 
groups, will provide qualitative information about any additive impact from text messaging.   
    Peer support for parents and youth: is not provided. Attending a peer support group would be difficult for 
this multi-ethnic sample, on top of busy families and working parents. Coaching youth and parent to develop 
identify individual support is intended to establish longer-term social support.   
    If intervention impact is not sustainable at 12 months: extended intensity of CHW support would require 
further testing. Post-intervention focus groups would identify subject recommendations for future trial design. 
 
G. Study Timeline 
Study Timeline* 
Y1 
Q1 
 
Q2 
 
Q3 
 
Q4 
Y2 
Q1 
 
Q2 
 
Q3 
 
Q4 
Y3 
Q1 
 
Q2 
 
Q3 
 
Q4 
Y4 
Q1 
 
Q2 
 
Q3 
 
Q4 
IRB review and 
Approval  
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hiring and training 
Coordinators 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hiring and training 
CHWs 
 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7-12 month 
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H. Dissemination Plan: will include multiple peer-reviewed publications and presentations at national 
meetings of experts represented by our multi-disciplinary team. We will continue to mutually co-inform the 
Sickle Cell Disease Association of America (SCDAA) regarding our respective multi-state CHW programs 
(LOS Banks) for program dissemination and shared efforts for enhancement and sustainability. Other 
partnerships will be developed to facilitate the adaptation of HABIT to other chronic pediatric conditions in 
underserved communities.

 
References 
 
1. 
Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4 
Suppl):S512-21. doi: 10.1016/j.amepre.2009.12.022. 
2. 
Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease 
in the United States: national and state estimates. Am J Hematol. 2010;85(1):77-8. doi: 10.1002/ajh.21570. 
3. 
Brousseau DC, Owens PL, Mosso AL, Panepinto JA, Steiner CA. Acute care utilization and 
rehospitalizations for sickle cell disease. JAMA. 2010;303(13):1288-94. doi: 10.1001/jama.2010.378. 
4. 
Raphael JL, Mei M, Mueller BU, Giordano T. High resource hospitalizations among children with vaso-
occlusive crises in sickle cell disease. Pediatr Blood Cancer. 2012;58(4):584-90. doi: 10.1002/pbc.23181. 
5. 
Lanzkron S, Carroll CP, Haywood C, Jr. Mortality rates and age at death from sickle cell disease: U.S., 
1979-2005. Public health reports. 2013;128(2):110-6. PubMed Central PMCID: PMC3560868. 
6. 
Hamideh D, Alvarez O. Sickle cell disease related mortality in the United States (1999-2009). Pediatr 
Blood Cancer. 2013;60(9):1482-6. doi: 10.1002/pbc.24557. 
7. 
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, 
Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, 
John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert 
panel members. JAMA. 2014;312(10):1033-48. doi: 10.1001/jama.2014.10517. 
8. 
McGann PT, Ware RE. Hydroxyurea for sickle cell anemia: what have we learned and what questions 
still remain? Curr Opin Hematol. 2011;18(3):158-65. doi: 10.1097/MOH.0b013e32834521dd. PubMed Central 
PMCID: PMCPMC3181131. 
9. 
Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 
2010;115(26):5300-11. doi: 10.1182/blood-2009-04-146852. PubMed Central PMCID: PMCPMC2902131. 
10. 
Candrilli SD, O'Brien SH, Ware RE, Nahata MC, Seiber EE, Balkrishnan R. Hydroxyurea adherence 
and associated outcomes among Medicaid enrollees with sickle cell disease. Am J Hematol. 2011;86(3):273-7. 
doi: 10.1002/ajh.21968. 
11. 
Brandow AM, Panepinto JA. Monitoring toxicity, impact, and adherence of hydroxyurea in children with 
sickle cell disease. Am J Hematol. 2011;86(9):804-6. doi: 10.1002/ajh.22101. PubMed Central PMCID: 
PMC3804029. 
12. 
Ritho J, Liu H, Hartzema AG, Lottenberg R. Hydroxyurea use in patients with sickle cell disease in a 
Medicaid population. Am J Hematol. 2011;86(10):888-90. doi: 10.1002/ajh.22134. 
13. 
Thornburg CD, Calatroni A, Telen M, Kemper AR. Adherence to hydroxyurea therapy in children with 
sickle cell anemia. J Pediatr. 2010;156(3):415-9. doi: 10.1016/j.jpeds.2009.09.044. PubMed Central PMCID: 
PMC3901082. 
14. 
Walsh KE, Cutrona SL, Kavanagh PL, Crosby LE, Malone C, Lobner K, Bundy DG. Medication 
adherence among pediatric patients with sickle cell disease: a systematic review. Pediatrics. 
2014;134(6):1175-83. doi: 10.1542/peds.2014-0177. PubMed Central PMCID: PMC4243064. 
15. 
Green NS, Manwani D, Qureshi M, Ireland K, Sinha A, Smaldone AM. Decreased fetal hemoglobin 
over time among youth with sickle cell disease on hydroxyurea is associated with higher urgent hospital use. 
Pediatr Blood Cancer. 2016. doi: 10.1002/pbc.26161. 
16. 
Bogart LM, Wagner G, Galvan FH, Banks D. Conspiracy beliefs about HIV are related to antiretroviral 
treatment nonadherence among african american men with HIV. Journal of acquired immune deficiency 
syndromes. 2010;53(5):648-55. doi: 10.1097/QAI.0b013e3181c57dbc. PubMed Central PMCID: PMC2845717. 
17. 
Simons LE, Blount RL. Identifying barriers to medication adherence in adolescent transplant recipients. 
Journal of pediatric psychology. 2007;32(7):831-44. doi: 10.1093/jpepsy/jsm030. 
18. 
Tapp H, Hebert L, Dulin M. Comparative effectiveness of asthma interventions within a practice based 
research network. BMC health services research. 2011;11:188. doi: 10.1186/1472-6963-11-188. PubMed 
Central PMCID: PMC3176175. 
19. 
Oyeku SO, Driscoll MC, Cohen HW, Trachtman R, Pashankar F, Mullen C, Giardina PJ, Velazco N, 
Racine AD, Green NS. Parental and other factors associated with hydroxyurea use for pediatric sickle cell 
disease. Pediatr Blood Cancer. 2013;60(4):653-8. doi: 10.1002/pbc.24381. PubMed Central PMCID: 
PMC3625668. 
20. 
McQuaid EL, Everhart RS, Seifer R, Kopel SJ, Mitchell DK, Klein RB, Esteban CA, Fritz GK, Canino G. 
Medication adherence among Latino and non-Latino white children with asthma. Pediatrics. 
2012;129(6):e1404-10. doi: 10.1542/peds.2011-1391. PubMed Central PMCID: PMC3362901. 

21. 
Delgado EM, Cho CS, Gildengorin G, Leibovich SA, Morris CR. Parental asthma education and risks 
for nonadherence to pediatric asthma treatments. Pediatric emergency care. 2014;30(11):782-7. doi: 
10.1097/PEC.0000000000000259. PubMed Central PMCID: PMC4591748. 
22. 
Wisk LE, Witt WP. Predictors of delayed or forgone needed health care for families with children. 
Pediatrics. 2012;130(6):1027-37. doi: 10.1542/peds.2012-0668. PubMed Central PMCID: PMC3507252. 
23. 
Reach G. Role of habit in adherence to medical treatment. Diabet Med. 2005;22(4):415-20. doi: 
10.1111/j.1464-5491.2004.01449.x. 
24. 
McGrady ME, Hommel KA. Medication adherence and health care utilization in pediatric chronic illness: 
a systematic review. Pediatrics. 2013;132(4):730-40. doi: 10.1542/peds.2013-1451. PubMed Central PMCID: 
PMCPMC3784296. 
25. 
Desai M, Oppenheimer JJ. Medication adherence in the asthmatic child and adolescent. Current allergy 
and asthma reports. 2011;11(6):454-64. doi: 10.1007/s11882-011-0227-2. 
26. 
Taddeo D, Egedy M, Frappier JY. Adherence to treatment in adolescents. Paediatr Child Health. 
2008;13(1):19-24. PubMed Central PMCID: PMCPMC2528818. 
27. 
Salema NE, Elliott RA, Glazebrook C. A systematic review of adherence-enhancing interventions in 
adolescents taking long-term medicines. The Journal of adolescent health : official publication of the Society 
for Adolescent Medicine. 2011;49(5):455-66. doi: 10.1016/j.jadohealth.2011.02.010. 
28. 
Quittner AL, Zhang J, Marynchenko M, Chopra PA, Signorovitch J, Yushkina Y, Riekert KA. Pulmonary 
medication adherence and health-care use in cystic fibrosis. Chest. 2014;146(1):142-51. doi: 
10.1378/chest.13-1926. 
29. 
Rothman RL, Mulvaney S, Elasy TA, VanderWoude A, Gebretsadik T, Shintani A, Potter A, Russell 
WE, Schlundt D. Self-management behaviors, racial disparities, and glycemic control among adolescents with 
type 2 diabetes. Pediatrics. 2008;121(4):e912-9. doi: 10.1542/peds.2007-1484. 
30. 
Saha S, Jacobs EA, Moore RD, Beach MC. Trust in physicians and racial disparities in HIV care. AIDS 
patient care and STDs. 2010;24(7):415-20. doi: 10.1089/apc.2009.0288. PubMed Central PMCID: 
PMC3472674. 
31. 
Smaldone A, Findley S, Bakken S, Matiz LA, Rosenthal SL, Jia H, Matos S, Manwani D, Green NS. 
Study protocol for a randomized controlled trial to assess the feasibility of an open label intervention to improve 
hydroxyurea adherence in youth with sickle cell disease. Contemporary clinical trials. 2016;49:134-42. doi: 
10.1016/j.cct.2016.06.004. 
32. 
Implementing NINR's Strategic Plan: Key Themes  [cited 2016 Sept. 16]. Available from: 
https://www.ninr.nih.gov/aboutninr/keythemes - .V-FtXbRbzpY. 
33. 
Disparities: HealthyPeople.gov;  [cited 2016 Sept. 20]. Available from: 
https://www.healthypeople.gov/2020/about/foundation-health-measures/Disparities. 
34. 
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-97. doi: 
10.1056/NEJMra050100. 
35. 
Iuga AO, McGuire MJ. Adherence and health care costs. Risk management and healthcare policy. 
2014;7:35-44. doi: 10.2147/RMHP.S19801. PubMed Central PMCID: PMC3934668. 
36. 
Asche C, LaFleur J, Conner C. A review of diabetes treatment adherence and the association with 
clinical and economic outcomes. Clin Ther. 2011;33(1):74-109. doi: 10.1016/j.clinthera.2011.01.019. 
37. 
Birmingham E, Catallozzi M, Findley SE, Vawdrey DK, Kukafka R, Stockwell MS. FluAlert: a qualitative 
evaluation of providers' desired characteristics and concerns regarding computerized influenza vaccination 
alerts. Preventive medicine. 2011;52(3-4):274-7. doi: 10.1016/j.ypmed.2011.01.008. 
38. 
Gielen AC, McDonald EM, Gary TL, Bone LR. Using the PRECEDE/PROCEED Model to apply health 
behavior theories. In: Glanz K, Rimer BK, Viswanath K, editors. Health Behavior and Health Education: 
Theory, Research and Practice. 4th ed. San Francisco, CA: Jossey-Bass; 2008. p. 407-33. 
39. 
Drotar D. Treatment adherence in patients with sickle cell anemia. J Pediatr. 2010;156(3):350-1. doi: 
10.1016/j.jpeds.2009.10.035. 
40. 
American Academy of P, American Academy of Family P, American College of P, Transitions Clinical 
Report Authoring G, Cooley WC, Sagerman PJ. Supporting the health care transition from adolescence to 
adulthood in the medical home. Pediatrics. 2011;128(1):182-200. doi: 10.1542/peds.2011-0969. 
41. 
Walders N, Drotar D, Kercsmar C. The allocation of family responsibility for asthma management tasks 
in African-American adolescents. The Journal of asthma : official journal of the Association for the Care of 
Asthma. 2000;37(1):89-99. 
42. 
DeBaun MR, Telfair J. Transition and sickle cell disease. Pediatrics. 2012;130(5):926-35. doi: 
10.1542/peds.2011-3049. 

43. 
Chaturvedi S, DeBaun MR. Evolution of sickle cell disease from a life-threatening disease of children to 
a chronic disease of adults: The last 40 years. Am J Hematol. 2016;91(1):5-14. doi: 10.1002/ajh.24235. 
44. 
Steiner CA, Miller JL. Sickle Cell Disease Patients in U.S. Hospitals, 2004: Statistical Brief #21.  
Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville (MD)2006. 
45. 
Blood disorders and blood safety: HealthyPeople.gov;  [cited 2016 Sept. 22]. Available from: 
https://www.healthypeople.gov/2020/topics-objectives/topic/blood-disorders-and-blood-safety/objectives. 
46. 
Strouse JJ, Heeney MM. Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, 
and management in children. Pediatr Blood Cancer. 2012;59(2):365-71. doi: 10.1002/pbc.24178. PubMed 
Central PMCID: PMCPMC3374046. 
47. 
Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, James AH, Laraque D, 
Mendez M, Montoya CJ, Pollock BH, Robinson L, Scholnik AP, Schori M. National Institutes of Health 
Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern 
Med. 2008;148(12):932-8. 
48. 
Darbari DS, Panepinto JA. What is the evidence that hydroxyurea improves health-related quality of life 
in patients with sickle cell disease? Hematology Am Soc Hematol Educ Program. 2012;2012:290-1. doi: 
10.1182/asheducation-2012.1.290. 
49. 
Fitzhugh CD, Hsieh MM, Allen D, Coles WA, Seamon C, Ring M, Zhao X, Minniti CP, Rodgers GP, 
Schechter AN, Tisdale JF, Taylor JGt. Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less 
Organ Damage and Longer Survival in Adults with Sickle Cell Anemia. PLoS One. 2015;10(11):e0141706. doi: 
10.1371/journal.pone.0141706. PubMed Central PMCID: PMC4648496. 
50. 
Smith WR, Ballas SK, McCarthy WF, Bauserman RL, Swerdlow PS, Steinberg MH, Waclawiw MA, 
Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell A. The association between hydroxyurea 
treatment and pain intensity, analgesic use, and utilization in ambulatory sickle cell anemia patients. Pain 
medicine. 2011;12(5):697-705. doi: 10.1111/j.1526-4637.2011.01096.x. 
51. 
Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W, Ataga K, Swerdlow P, 
Kutlar A, DeCastro L, Waclawiw MA, Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell A, 
Follow-Up MSHP. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year 
follow-up. Am J Hematol. 2010;85(6):403-8. doi: 10.1002/ajh.21699. PubMed Central PMCID: PMC2879711. 
52. 
Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, Sinopoulou K, 
Balassopoulou A, Loukopoulos D, Terpos E. The effect of prolonged administration of hydroxyurea on 
morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial 
(LaSHS). Blood. 2010;115(12):2354-63. doi: 10.1182/blood-2009-05-221333. 
53. 
Peretz PJ, Matiz LA, Findley S, Lizardo M, Evans D, McCord M. Community health workers as drivers 
of a successful community-based disease management initiative. Am J Public Health. 2012;102(8):1443-6. doi: 
10.2105/AJPH.2011.300585. PubMed Central PMCID: PMCPMC3464827. 
54. 
Uwemedimo OT, Arora G, Russ CM. New views on global child health: global solutions for care of 
vulnerable children in the United States. Curr Opin Pediatr. 2016;28(5):667-72. doi: 
10.1097/MOP.0000000000000402. 
55. 
Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362-9. doi: 
10.1056/NEJMct0708272. 
56. 
Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, Ware RE. Sustained 
long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. 
Blood. 2004;103(6):2039-45. doi: 10.1182/blood-2003-07-2475. 
57. 
Hankins JS, Aygun B, Nottage K, Thornburg C, Smeltzer MP, Ware RE, Wang WC. From infancy to 
adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Medicine 
(Baltimore). 2014;93(28):e215. doi: 10.1097/MD.0000000000000215. PubMed Central PMCID: 
PMCPMC4603125. 
58. 
Ferster A, Tahriri P, Vermylen C, Sturbois G, Corazza F, Fondu P, Devalck C, Dresse MF, Feremans 
W, Hunninck K, Toppet M, Philippet P, Van Geet C, Sariban E. Five years of experience with hydroxyurea in 
children and young adults with sickle cell disease. Blood. 2001;97(11):3628-32. 
59. 
Naar-King S, Montepiedra G, Nichols S, Farley J, Garvie PA, Kammerer B, Malee K, Sirois PA, Storm 
D, Team PP. Allocation of family responsibility for illness management in pediatric HIV. Journal of pediatric 
psychology. 2009;34(2):187-94. doi: 10.1093/jpepsy/jsn065. PubMed Central PMCID: PMC2722122. 
60. 
Anderson B, Ho J, Brackett J, Finkelstein D, Laffel L. Parental involvement in diabetes management 
tasks: relationships to blood glucose monitoring adherence and metabolic control in young adolescents with 
insulin-dependent diabetes mellitus. J Pediatr. 1997;130(2):257-65. 

61. 
McQuaid EL, Kopel SJ, Klein RB, Fritz GK. Medication adherence in pediatric asthma: reasoning, 
responsibility, and behavior. Journal of pediatric psychology. 2003;28(5):323-33. 
62. 
Orrell-Valente JK, Jarlsberg LG, Hill LG, Cabana MD. At what age do children start taking daily asthma 
medicines on their own? Pediatrics. 2008;122(6):e1186-92. doi: 10.1542/peds.2008-0292. 
63. 
Anderson BJ, Auslander WF, Jung KC, Miller JP, Santiago JV. Assessing family sharing of diabetes 
responsibilities. Journal of pediatric psychology. 1990;15(4):477-92. 
64. 
Treadwell MJ, Law AW, Sung J, Hackney-Stephens E, Quirolo K, Murray E, Glendenning GA, 
Vichinsky E. Barriers to adherence of deferoxamine usage in sickle cell disease. Pediatr Blood Cancer. 
2005;44(5):500-7. doi: 10.1002/pbc.20290. 
65. 
Anderson BJ, Brackett J, Ho J, Laffel LM. An office-based intervention to maintain parent-adolescent 
teamwork in diabetes management. Impact on parent involvement, family conflict, and subsequent glycemic 
control. Diabetes Care. 1999;22(5):713-21. 
66. 
Findley SE, Matos S, Hicks AL, Campbell A, Moore A, Diaz D. Building a consensus on community 
health workers' scope of practice: lessons from New York. Am J Public Health. 2012;102(10):1981-7. doi: 
10.2105/AJPH.2011.300566. PubMed Central PMCID: PMCPMC3490670. 
67. 
Ayala GX, Vaz L, Earp JA, Elder JP, Cherrington A. Outcome effectiveness of the lay health advisor 
model among Latinos in the United States: an examination by role. Health Educ Res. 2010;25(5):815-40. doi: 
10.1093/her/cyq035. PubMed Central PMCID: PMCPMC2948840. 
68. 
Allen JK, Himmelfarb CR, Szanton SL, Bone L, Hill MN, Levine DM. COACH trial: a randomized 
controlled trial of nurse practitioner/community health worker cardiovascular disease risk reduction in urban 
community health centers: rationale and design. Contemporary clinical trials. 2011;32(3):403-11. doi: 
10.1016/j.cct.2011.01.001. PubMed Central PMCID: PMCPMC3070050. 
69. 
Stockwell MS, Kharbanda EO, Martinez RA, Vargas CY, Vawdrey DK, Camargo S. Effect of a text 
messaging intervention on influenza vaccination in an urban, low-income pediatric and adolescent population: 
a randomized controlled trial. JAMA. 2012;307(16):1702-8. doi: 10.1001/jama.2012.502. 
70. 
Stockwell MS, Kharbanda EO, Martinez RA, Lara M, Vawdrey D, Natarajan K, Rickert VI. Text4Health: 
impact of text message reminder-recalls for pediatric and adolescent immunizations. Am J Public Health. 
2012;102(2):e15-21. doi: 10.2105/AJPH.2011.300331. PubMed Central PMCID: PMCPMC3483980. 
71. 
Estepp JH, Winter B, Johnson M, Smeltzer MP, Howard SC, Hankins JS. Improved hydroxyurea effect 
with the use of text messaging in children with sickle cell anemia. Pediatr Blood Cancer. 2014;61(11):2031-6. 
doi: 10.1002/pbc.25177. 
72. 
Smaldone A, Stockwell MS, Osborne JC, Cortes Y, Bekele E, Green NS. Adolescent and parent use of 
new technologies for health communication: a study in an urban latino community. Journal of public health 
research. 2015;4(1):376. doi: 10.4081/jphr.2015.376. PubMed Central PMCID: PMC4407036. 
73. 
Stockwell MS, Westhoff C, Kharbanda EO, Vargas CY, Camargo S, Vawdrey DK, Castano PM. 
Influenza vaccine text message reminders for urban, low-income pregnant women: a randomized controlled 
trial. Am J Public Health. 2014;104 Suppl 1:e7-12. doi: 10.2105/AJPH.2013.301620. PubMed Central PMCID: 
PMC4011110. 
74. 
Gellad WF, Haas JS, Safran DG. Race/ethnicity and nonadherence to prescription medications among 
seniors: results of a national study. Journal of general internal medicine. 2007;22(11):1572-8. doi: 
10.1007/s11606-007-0385-z. PubMed Central PMCID: PMC2219813. 
75. 
Pai AL, Drotar D. Treatment adherence impact: the systematic assessment and quantification of the 
impact of treatment adherence on pediatric medical and psychological outcomes. Journal of pediatric 
psychology. 2010;35(4):383-93. doi: 10.1093/jpepsy/jsp073. 
76. 
Anders DG, Tang F, Ledneva T, Caggana M, Green NS, Wang Y, Sturman LS. Hydroxyurea Use in 
Young Children With Sickle Cell Anemia in New York State. Am J Prev Med. 2016;51(1 Suppl 1):S31-8. doi: 
10.1016/j.amepre.2016.01.001. 
77. 
Hood KK, Rohan JM, Peterson CM, Drotar D. Interventions with adherence-promoting components in 
pediatric type 1 diabetes: meta-analysis of their impact on glycemic control. Diabetes Care. 2010;33(7):1658-
64. doi: 10.2337/dc09-2268. PubMed Central PMCID: PMC2890378. 
78. 
Kahana S, Drotar D, Frazier T. Meta-analysis of psychological interventions to promote adherence to 
treatment in pediatric chronic health conditions. Journal of pediatric psychology. 2008;33(6):590-611. doi: 
10.1093/jpepsy/jsm128. 
79. 
Creary SE, Gladwin MT, Byrne M, Hildesheim M, Krishnamurti L. A pilot study of electronic directly 
observed therapy to improve hydroxyurea adherence in pediatric patients with sickle-cell disease. Pediatr 
Blood Cancer. 2014;61(6):1068-73. doi: 10.1002/pbc.24931. 

80. 
Inoue S, Kodjebacheva G, Scherrer T, Rice G, Grigorian M, Blankenship J, Onwuzurike N. Adherence 
to hydroxyurea medication by children with sickle cell disease (SCD) using an electronic device: a feasibility 
study. Int J Hematol. 2016;104(2):200-7. doi: 10.1007/s12185-016-2027-x. 
81. 
Bruzzese JM, Kingston S, Sheares BJ, Cespedes A, Sadeghi H, Evans D. Feasibility and preliminary 
outcomes of a school-based intervention for inner-city, ethnic minority adolescents with undiagnosed asthma. 
Patient education and counseling. 2011;85(2):290-4. doi: 10.1016/j.pec.2010.09.019. PubMed Central PMCID: 
PMC3029508. 
82. 
Bruzzese JM, Reigada LC, Lamm A, Wang J, Li M, Zandieh SO, Klein RG. Association of Youth and 
Caregiver Anxiety and Asthma Care Among Urban Young Adolescents. Acad Pediatr. 2016. doi: 
10.1016/j.acap.2016.03.009. 
83. 
Bruzzese JM, Sheares BJ, Vincent EJ, Du Y, Sadeghi H, Levison MJ, Mellins RB, Evans D. Effects of a 
school-based intervention for urban adolescents with asthma. A controlled trial. American journal of respiratory 
and critical care medicine. 2011;183(8):998-1006. doi: 10.1164/rccm.201003-0429OC. PubMed Central 
PMCID: PMC3086747. 
84. 
Bruzzese JM, Unikel L, Gallagher R, Evans D, Colland V. Feasibility and impact of a school-based 
intervention for families of urban adolescents with asthma: results from a randomized pilot trial. Family 
process. 2008;47(1):95-113. 
85. 
Stockwell MS, Hofstetter AM, DuRivage N, Barrett A, Fernandez N, Vargas CY, Camargo S. Text 
message reminders for second dose of influenza vaccine: a randomized controlled trial. Pediatrics. 
2015;135(1):e83-91. doi: 10.1542/peds.2014-2475. PubMed Central PMCID: PMC4279072. 
86. 
Dampier C, Barry V, Gross HE, Lui Y, Thornburg CD, DeWalt DA, Reeve BB. Initial Evaluation of the 
Pediatric PROMIS(R) Health Domains in Children and Adolescents With Sickle Cell Disease. Pediatr Blood 
Cancer. 2016;63(6):1031-7. doi: 10.1002/pbc.25944. PubMed Central PMCID: PMC4833539. 
87. 
Dampier C, Jaeger B, Gross HE, Barry V, Edwards L, Lui Y, DeWalt DA, Reeve BB. Responsiveness of 
PROMIS(R) Pediatric Measures to Hospitalizations for Sickle Pain and Subsequent Recovery. Pediatr Blood 
Cancer. 2016;63(6):1038-45. doi: 10.1002/pbc.25931. 
88. 
Wang W, Brugnara C, Snyder C, Wynn L, Rogers Z, Kalinyak K, Brown C, Qureshi A, Bigelow C, 
Neumayr L, Smith-Whitley K, Chui DH, Delahunty M, Woolson R, Steinberg M, Telen M, Kesler K. The effects 
of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial. 
Br J Haematol. 2011;152(6):771-6. doi: 10.1111/j.1365-2141.2010.08523.x. 
89. 
Panepinto JA, Torres S, Bendo CB, McCavit TL, Dinu B, Sherman-Bien S, Bemrich-Stolz C, Varni JW. 
PedsQL sickle cell disease module: feasibility, reliability, and validity. Pediatr Blood Cancer. 2013;60(8):1338-
44. doi: 10.1002/pbc.24491. PubMed Central PMCID: PMC4412167. 
90. 
Grey M, Knafl K, McCorkle R. A framework for the study of self- and family management of chronic 
conditions. Nurs Outlook. 2006;54(5):278-86. doi: 10.1016/j.outlook.2006.06.004. 
91. 
Grey M, Schulman-Green D, Knafl K, Reynolds NR. A revised Self- and Family Management 
Framework. Nurs Outlook. 2015;63(2):162-70. doi: 10.1016/j.outlook.2014.10.003. 
92. 
Ingerski LM, Anderson BJ, Dolan LM, Hood KK. Blood glucose monitoring and glycemic control in 
adolescence: contribution of diabetes-specific responsibility and family conflict. The Journal of adolescent 
health : official publication of the Society for Adolescent Medicine. 2010;47(2):191-7. doi: 
10.1016/j.jadohealth.2010.01.012. PubMed Central PMCID: PMCPMC2907244. 
93. 
Helgeson VS, Reynolds KA, Siminerio L, Escobar O, Becker D. Parent and adolescent distribution of 
responsibility for diabetes self-care: links to health outcomes. Journal of pediatric psychology. 2008;33(5):497-
508. doi: 10.1093/jpepsy/jsm081. PubMed Central PMCID: PMC3442285. 
94. 
Slawta JN, DeNeui D. Be a Fit Kid: nutrition and physical activity for the fourth grade. Health Promot 
Pract. 2010;11(4):522-9. doi: 10.1177/1524839908328992. 
95. 
Cole RE, Horacek T. Applying precede-proceed to develop an intuitive eating nondieting approach to 
weight management pilot program. J Nutr Educ Behav. 2009;41(2):120-6. doi: 10.1016/j.jneb.2008.03.006. 
96. 
Manios Y, Grammatikaki E, Androutsos O, Chinapaw MJ, Gibson EL, Buijs G, Iotova V, Socha P, 
Annemans L, Wildgruber A, Mouratidou T, Yngve A, Duvinage K, de Bourdeaudhuij I, ToyBox-study g. A 
systematic approach for the development of a kindergarten-based intervention for the prevention of obesity in 
preschool age children: the ToyBox-study. Obesity reviews : an official journal of the International Association 
for the Study of Obesity. 2012;13 Suppl 1:3-12. doi: 10.1111/j.1467-789X.2011.00974.x. 
97. 
Reid ME, El Beshlawy A, Inati A, Kutlar A, Abboud MR, Haynes J, Jr., Ward R, Sharon B, Taher AT, 
Smith W, Manwani D, Ghalie RG. A double-blind, placebo-controlled phase II study of the efficacy and safety 

of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am J Hematol. 
2014;89(7):709-13. doi: 10.1002/ajh.23725. 
98. 
Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen 
W, Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller 
ST, Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA, 
Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, Luden 
J, Mortier NA, Stuber SE, Luban NL, Cohen AR, Pressel S, Adams RJ. Hydroxycarbamide versus chronic 
transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD 
With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. 
Lancet. 2016;387(10019):661-70. doi: 10.1016/S0140-6736(15)01041-7. 
99. 
Bajwa R, Schechter T, Soni S, Gassas A, Doyle J, Sisler I, Godder K, Tatman D, Rumelhart S, Domm 
J, Miao Y, Frangoul H. Outcome of children who experience disease relapse following allogeneic 
hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant. 2013;48(5):661-5. doi: 
10.1038/bmt.2012.209. 
100. 
Haywood C, Jr., Bediako S, Lanzkron S, Diener-West M, Strouse J, Haythornthwaite J, Onojobi G, 
Beach MC, Investigators I. An unequal burden: poor patient-provider communication and sickle cell disease. 
Patient education and counseling. 2014;96(2):159-64. doi: 10.1016/j.pec.2014.05.013. PubMed Central 
PMCID: PMC4115582. 
101. 
Haywood C, Jr., Diener-West M, Strouse J, Carroll CP, Bediako S, Lanzkron S, Haythornthwaite J, 
Onojobi G, Beach MC, Investigators I, Investigators I. Perceived discrimination in health care is associated with 
a greater burden of pain in sickle cell disease. Journal of pain and symptom management. 2014;48(5):934-43. 
doi: 10.1016/j.jpainsymman.2014.02.002. PubMed Central PMCID: PMC4198520. 
102. 
Haywood C, Jr., Lanzkron S, Bediako S, Strouse JJ, Haythornthwaite J, Carroll CP, Diener-West M, 
Onojobi G, Beach MC, Investigators I. Perceived discrimination, patient trust, and adherence to medical 
recommendations among persons with sickle cell disease. Journal of general internal medicine. 
2014;29(12):1657-62. doi: 10.1007/s11606-014-2986-7. PubMed Central PMCID: PMC4242876. 
103. 
Haywood C, Jr., Lanzkron S, Diener-West M, Haythornthwaite J, Strouse JJ, Bediako S, Onojobi G, 
Beach MC, for the II. Attitudes toward clinical trials among patients with sickle cell disease. Clinical trials. 
2014;11(3):275-83. doi: 10.1177/1740774513519876. PubMed Central PMCID: PMC4387103. 
104. 
Stevens EM, Patterson CA, Li YB, Smith-Whitley K, Barakat LP. Mistrust of Pediatric Sickle Cell 
Disease Clinical Trials Research. Am J Prev Med. 2016;51(1 Suppl 1):S78-86. doi: 
10.1016/j.amepre.2016.01.024. PubMed Central PMCID: PMC4916926. 
105. 
Ware RE, Eggleston B, Redding-Lallinger R, Wang WC, Smith-Whitley K, Daeschner C, Gee B, Styles 
LA, Helms RW, Kinney TR, Ohene-Frempong K. Predictors of fetal hemoglobin response in children with sickle 
cell anemia receiving hydroxyurea therapy. Blood. 2002;99(1):10-4. 
106. 
Kharbanda EO, Stockwell MS, Fox HW, Rickert VI. Text4Health: a qualitative evaluation of parental 
readiness for text message immunization reminders. Am J Public Health. 2009;99(12):2176-8. doi: 
10.2105/AJPH.2009.161364. PubMed Central PMCID: PMCPMC2775765. 
107. 
Kharbanda EO, Vargas CY, Castano PM, Lara M, Andres R, Stockwell MS. Exploring pregnant 
women's views on influenza vaccination and educational text messages. Preventive medicine. 2011;52(1):75-
7. doi: 10.1016/j.ypmed.2010.10.009. 
108. 
Tolan PH, Gorman-Smith D, Henry D, Schoeny M. The benefits of booster interventions: evidence from 
a family-focused prevention program. Prev Sci. 2009;10(4):287-97. doi: 10.1007/s11121-009-0139-8. 
109. 
Varni JW, Stucky BD, Thissen D, Dewitt EM, Irwin DE, Lai JS, Yeatts K, Dewalt DA. PROMIS Pediatric 
Pain Interference Scale: an item response theory analysis of the pediatric pain item bank. The journal of pain : 
official journal of the American Pain Society. 2010;11(11):1109-19. doi: 10.1016/j.jpain.2010.02.005. PubMed 
Central PMCID: PMC3129595. 
110. 
Lai JS, Stucky BD, Thissen D, Varni JW, DeWitt EM, Irwin DE, Yeatts KB, DeWalt DA. Development 
and psychometric properties of the PROMIS((R)) pediatric fatigue item banks. Quality of life research : an 
international journal of quality of life aspects of treatment, care and rehabilitation. 2013;22(9):2417-27. doi: 
10.1007/s11136-013-0357-1. PubMed Central PMCID: PMC3695011. 
111. 
Irwin DE, Gross HE, Stucky BD, Thissen D, DeWitt EM, Lai JS, Amtmann D, Khastou L, Varni JW, 
DeWalt DA. Development of six PROMIS pediatrics proxy-report item banks. Health and quality of life 
outcomes. 2012;10:22. doi: 10.1186/1477-7525-10-22. PubMed Central PMCID: PMC3312870. 
112. 
DeWalt DA, Gross HE, Gipson DS, Selewski DT, DeWitt EM, Dampier CD, Hinds PS, Huang IC, 
Thissen D, Varni JW. PROMIS((R)) pediatric self-report scales distinguish subgroups of children within and 

across six common pediatric chronic health conditions. Quality of life research : an international journal of 
quality of life aspects of treatment, care and rehabilitation. 2015;24(9):2195-208. doi: 10.1007/s11136-015-
0953-3. PubMed Central PMCID: PMC4531096. 
113. 
Anderson BJ, Vangsness L, Connell A, Butler D, Goebel-Fabbri A, Laffel LM. Family conflict, 
adherence, and glycaemic control in youth with short duration Type 1 diabetes. Diabet Med. 2002;19(8):635-
42. 
114. 
Anderson BJ, Holmbeck G, Iannotti RJ, McKay SV, Lochrie A, Volkening LK, Laffel L. Dyadic measures 
of the parent-child relationship during the transition to adolescence and glycemic control in children with type 1 
diabetes. Families, systems & health : the journal of collaborative family healthcare. 2009;27(2):141-52. doi: 
10.1037/a0015759. PubMed Central PMCID: PMC2843423. 
115. 
Hsin O, La Greca AM, Valenzuela J, Moine CT, Delamater A. Adherence and glycemic control among 
Hispanic youth with type 1 diabetes: role of family involvement and acculturation. Journal of pediatric 
psychology. 2010;35(2):156-66. doi: 10.1093/jpepsy/jsp045. PubMed Central PMCID: PMC2821010. 
116. 
McQuaid EL, Penza-Clyve SM, Nassau JH, Fritz GK, Klein R, O'Connor S, Wamboldt F, Gavin F. The 
asthma responsibility questionnaire: Patterns of family responsibilty for asthma management. Chilren's Health 
Care. 2010;30:183-99. 
117. 
Greenley RN, Doughty A, Stephens M, Kugathasan S. Brief report: development of the inflammatory 
bowel disease family responsibility questionnaire. Journal of pediatric psychology. 2010;35(2):183-7. doi: 
10.1093/jpepsy/jsp052. 
118. 
Smaldone A, Tsimicalis A, Stone PW. Measuring resource utilization in patient-oriented comparative 
effectiveness research: a psychometric study of the Resource Utilization Questionnaire. Research and theory 
for nursing practice. 2011;25(2):80-106. PubMed Central PMCID: PMC3237636. 
119. 
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory 
version 4.0 generic core scales in healthy and patient populations. Medical care. 2001;39(8):800-12. 
120. 
Thornburg CD, Calatroni A, Panepinto JA. Differences in health-related quality of life in children with 
sickle cell disease receiving hydroxyurea. J Pediatr Hematol Oncol. 2011;33(4):251-4. doi: 
10.1097/MPH.0b013e3182114c54. PubMed Central PMCID: PMCPMC3729442. 
121. 
Dale JC, Cochran CJ, Roy L, Jernigan E, Buchanan GR. Health-related quality of life in children and 
adolescents with sickle cell disease. Journal of pediatric health care : official publication of National Association 
of Pediatric Nurse Associates & Practitioners. 2011;25(4):208-15. doi: 10.1016/j.pedhc.2009.12.006. PubMed 
Central PMCID: PMC3124665. 
122. 
McClellan CB, Schatz J, Sanchez C, Roberts CW. Validity of the Pediatric Quality Of Life Inventory for 
youth with sickle cell disease. Journal of pediatric psychology. 2008;33(10):1153-62. doi: 
10.1093/jpepsy/jsn036. 
123. 
Panepinto JA, Pajewski NM, Foerster LM, Hoffmann RG. The performance of the PedsQL generic core 
scales in children with sickle cell disease. J Pediatr Hematol Oncol. 2008;30(9):666-73. doi: 
10.1097/MPH.0b013e31817e4a44. PubMed Central PMCID: PMC2667700. 
124. 
Poghosyan L, Nannini A, Smaldone A, Clarke S, O'Rourke NC, Rosato BG, Berkowitz B. Revisiting 
scope of practice facilitators and barriers for primary care nurse practitioners: a qualitative investigation. Policy, 
politics & nursing practice. 2013;14(1):6-15. doi: 10.1177/1527154413480889. 
125. 
Ritholz MD, Smaldone A, Lee J, Castillo A, Wolpert H, Weinger K. Perceptions of psychosocial factors 
and the insulin pump. Diabetes Care. 2007;30(3):549-54. doi: 10.2337/dc06-1755. 
126. 
Smaldone A, Ritholz MD. Perceptions of parenting children with type 1 diabetes diagnosed in early 
childhood. Journal of pediatric health care : official publication of National Association of Pediatric Nurse 
Associates & Practitioners. 2011;25(2):87-95. doi: 10.1016/j.pedhc.2009.09.003. PubMed Central PMCID: 
PMC3053084.