Qasba 1

Easha Qasba

Ms. Chawkat

Independent Research II GT

23 March 2017

Data Analysis

Due to the limitations of the researcher, meta-analysis was used to gather data from

various scholarly sources regarding the characteristics of Sickle Cell Disease as well as the

various treatment options. Between the various sources, different information regarding the

adherence of caregivers to prescribed treatment protocols was given, and theories regarding

improving patient care presented differing perspectives.

In order to combat the organ damage and decrease the frequency of pain crises and other

incidents, treatments such as hydroxyurea and prophylactic penicillin are proven to be useful. In

source 1, The National Heart, Lung, and Blood Institute found that a daily dose of penicillin in

SCD patients between the age of 3 months and 3 years can reduce the incidence of infection by

84%. The success of prophylactic penicillin in such young children encouraged scientists and

legislators to push for newborn screenings for blood disorders in order to start treatment earlier.

Over the course of several years, 44 states made newborn screenings available or mandatory

versus the previous 14 states. In 1991, a trial testing hydroxyurea found that this treatment

reduced by half the following: pain crises, hospitalizations, acute chest syndrome episodes, and

units of blood needed. It was even found that, in patients between 5 and 15, hydroxyurea

therapies increased fetal hemoglobin levels and decreased complications along with the other

benefits mentioned earlier. Bone marrow transplants, while risky for the patient and only

considered in extreme cases, has been extremely successful in some cases. New research
 Qasba 2

indicates the use of the umbilical cord could be a better option since it negates the need for

chemotherapy.

While the National Institutes of Health seem highly optimistic about the future of

treatment for the disease, the other sources expressed concern about the inconsistency in patient

care which was essentially undermining the treatment plans and best possible outcomes.

Considering the awareness for this disease in relatively low and the fact that it only received

government funding for research about three decades ago, the progress made has been

substantial. The progress would be greatly improved by greater adherence.

Overall, while researchers have not yet found a cure for SCD, they are working towards

several treatments that offer a longer life expectancy and a better quality of life than before.

While the researcher began this investigation under the impression that there were insufficient

treatment, this assumption was incorrect; however, a large amount of money was needed to make

this progress and more will be needed in order to progress towards a cure. This data revealed

what is truly missing from the field, what progress has already been made, and what realistic

possibilities still exist within the research community. It is important to acknowledge what has

been accomplished thus far; however, the standard of care is not consistent which is something

that can be improved.

Source comparison:

Title Findings Relation to Research

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Sickle Cell Life expectancy The life expectancy

Research for has doubled since 1975 increased because of
Treatment and Cure Gene therapy is treatment development, but
being developed as a the average is still 35 years
treatment less than the average
Reasons for American
variability in disease is The progress:
still unknown effective treatment protocols
Hydroxyurea Still to be done:
therapy causes for variability
Acute chest
syndrome
Org
an damage
Penicillin
prophylaxis

Source 2 They conducted This combined the

an experiment with a
multi-stage plan for
treatment in order to
determine the effects over
the course of 1 year. The
goals was an incident free
year
RRT was
implicated in 83% of
grade 3-5 adverse events
despite medication
standard treatment of
penicillin prophylaxis with
several other treatments
including a surgical graft
implantation.
Compl
ications still occurred
The 1-
year EFS was 76%
(95% CI, 56-88) and
the 1-year overall
survival was 86%
At
data cutoff in March
2016, the 2-year EFS
was 69% (95% CI,
48-82) and the 2-year
overall survival was
79%
Since this is a
procedure conducted in
hospital (at least at first),
there is a greater adherence
which lended good
outcomes.

A trial of unrelated This study created this is the basis for

donor marrow a questionnaire in order to my research as it shows that
 Qasba 4

transplantation for assess adherence to the the treatments can be highly

children with treatment protocols. effective if used diligently,
severe sickle cell Data was taken but adherence was lower
disease from primary caregivers, than expected.
physicians, and There were deaths
pharmacists who even among those who
distributed the drugs adhered
For those with limits
better adherence, they had to what medicine can
better results overcome.
Adherence was
lower than expected- on
average

50 Years in Basics of the what is the basis and

Hematology disease history of the disease
Demographic This states that the
information field needs to develop safer,
prophylactic more effective drugs, but it is
penicillin impossible to truly see the
bone marrow effect of the treatments if
transplant they are not carried out
hydroxyurea diligently.
Thalassemia
Transfusions
whats needed:
safer, more effective
drugs
 Qasba 5

Sources:

Source 2:
http://www.bloodjournal.org/content/128/21/2561?sso-checked=true
Abstract
Children with sickle cell disease experience organ damage, impaired quality of life,
and premature mortality. Allogeneic bone marrow transplant from an HLA-matched
sibling can halt disease progression but is limited by donor availability. A Blood and
Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from
2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation.
The primary objective was 1-year event-free survival (EFS) after HLA allele-matched
(at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning
regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host
disease (GVHD) prophylaxis included calcineurin inhibitor, short-course
methotrexate, and methylprednisolone. Transplant indications included stroke (n =
12), transcranial Doppler velocity >200 cm/s (n = 2), 3 vaso-occlusive pain crises per
year (n = 12), or 2 acute chest syndrome episodes (n = 4) in the 2 years preceding
enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection
was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The
corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate
of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD
was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34%
incidence of posterior reversible encephalopathy syndrome was noted in the first 6
months. Although the 1-year EFS met the prespecified target of 75%, this regimen
cannot be considered sufficiently safe for widespread adoption without modifications
to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered
at www.clinicaltrials.gov as #NCT00745420.

Introduction
Sickle cell disease (SCD) is a monogenic hemoglobin disorder characterized by hemolytic
anemia with variable clinical manifestations after endothelial damage and vasculopathy.1
Hypoperfusion results in multiple organ damage. In patients with severe disease, symptoms
manifest early and progress during childhood. Allogeneic hematopoietic cell transplantation can
replace sickle erythropoiesis. The results of HLA-matched sibling donor transplants are
excellent, with event-free survival (EFS) in excess of 90% and with acceptable rates of graft
rejection (GR) and graft-versus-host disease (GVHD).2-5 HLA-matched sibling donor
transplants account for the majority of transplants performed worldwide for
hemoglobinopathy.6,7 However, only 18% of patients with SCD have an HLA-matched sibling
donor in the United States.8 HLA-matched adult unrelated donors (URDs) have been used to
 Qasba 6

expand the donor pool for nonmalignant hematologic disorders, but their role in SCD transplants
is unclear.9-11 Although the likelihood of finding an HLA-matched URD for African
Americans is low at 16% to 19%, utilization of these donors does expand the donor pool.12 To
date, most SCD transplants have used myeloablative conditioning regimens, but these can result
in toxicities such as growth inhibition, gonadal hypofunction, and sterility.13-16 Reduced-
intensity conditioning (RIC) regimens, although associated with a more favorable toxicity
profile, can be associated with higher rates of GR, especially with graft sources such as umbilical
cord blood.17-20 A RIC regimen augmented with host immunoablation by alemtuzumab was
previously successful in achieving donor engraftment.21,22 In that report of HLA-matched
sibling donor bone marrow transplant (BMT) in 52 children with hemoglobinopathies, acute and
chronic GVHD rates were 23% and 13%, respectively.21 The regimen was adopted for a phase 2
URD transplant trial with bone marrow or umbilical cord blood grafts through the Blood and
Marrow Transplant Clinical Trials Network (BMT CTN #0601; NCT 00745420). This report
describes outcomes from the trial using bone marrow grafts. The umbilical cord blood arm was
closed early after a high GR rate.19

Methods
Study design
The primary end point was 1-year EFS; death from any cause, GR, or recurrent disease was
considered an event. Prespecified secondary end points included overall survival, hematopoietic
recovery, acute and chronic GVHD, infections, hepatic sinusoidal syndrome, interstitial
pneumonitis, seizure, posterior reversible encephalopathy syndrome (PRES), and health-related
quality of life (HRQL). The trial opened on 11 April 2008 and closed to enrollment on 24 April
2014. Enrollment was paused once for clarification of HLA typing requirements once (for 6
months) during this period. This analysis includes data collected as of March 2016. The median
follow-up of surviving patients was 26 months (range, 12-62 months). All patients were followed
for at least 24 months, except for 1 patient who was lost to follow-up at 12 months.

Patients
The protocol was approved by the institutional review board at each of the
participating institutions. Informed consent was obtained from parents or from
patients aged >18 years, and assent was obtained from patients aged 7-18 years before
enrollment. The consent form extensively described alternate conservative treatment
approaches for SCD, as well as the pros and cons of transplant. Trial eligibility was
confirmed by 3 independent hematologists. Eligible patients were aged 3.0 to 20 years
who had severe SCD indicated by 1 or more the following: (1) clinically significant
neurologic event (stroke) or any neurologic defect lasting >24 hours and accompanied
by an infarct on cerebral magnetic resonance imaging; (2) a transcranial Doppler
velocity >200 cm/s by the nonimaging technique, or velocity that exceeded 185 cm/s
by the imaging technique measured at a minimum of 2 separate occasions 1 month or
more apart23; (3) a minimum of 2 episodes of acute chest syndrome within the
preceding 2-year period and defined as new pulmonary alveolar consolidation
 Qasba 7

involving at least 1 complete lung segment despite adequate supportive care

measures; and (4) minimum of 3 new pain events per year in the previous 2 years and
defined as new onset of pain lasting for at least 2 hours, for which there was no other
explanation, and occurred despite adequate supportive care measures. Adequate
organ function pretransplant required the following: serum creatinine levels <1.5
times the upper limit of normal for age and the glomerular filtration rate >100 mL/min
per 1.73 m2 or adjusted for age; alanine aminotransferase and aspartate
aminotransferase <5 times the upper limit of normal and direct serum bilirubin <2
times the upper limit of normal; left ventricular ejection fraction >40% or left
ventricular shortening fraction >26%; and diffusing capacity of the lungs for carbon
monoxide >40% of predicted (corrected for hemoglobin). Patients with serum ferritin
>1000 ng/mL were required to have a liver biopsy demonstrating the absence of
cirrhosis and bridging fibrosis if they had received regular red cell transfusions for >1
year. Hemoglobin S level was maintained at 45% within 7 days of initiation of
transplant conditioning, and chelation and/or hydroxyurea were discontinued 48
hours before initiation of conditioning. Ineligible patients included those with an
HLA-matched sibling, HIV seropositivity, a performance score <40, and uncontrolled
bacterial, viral, or fungal infection.

Treatment
The conditioning regimen included alemtuzumab, fludarabine, and melphalan, with
the alemtuzumab administered between day 22 and day 18 before graft infusion to
achieve host immunoablation (Table 1). Prophylaxis for GVHD consisted of a
calcineurin inhibitor (tacrolimus or cyclosporine) administered from day 3 through
day 100 after graft infusion, with subsequent taper through day 180; methotrexate 7.5
mg/m2 on days 1, 3, and 6; and methylprednisolone 1 mg/kg per day from days 7
through 28, with subsequent taper by 20% per week. Supportive care
recommendations included granulocyte colony-stimulating factor commenced on
day 7 and continued until an absolute neutrophil count of 1.5 109/L on 3 days after
the nadir, weekly surveillance for cytomegalovirus and Epstein-Barr virus reactivation,
seizure prophylaxis for the duration of use of calcineurin inhibitors, strict blood
pressure control, preemptive therapy for viral infections, bacterial prophylaxis
through day 100, and prompt treatment of overt or suspected infections. To mitigate
the risk of intracranial hemorrhage, platelet count was maintained at 50 109/L.24

Treatment regimen
Outcomes
The primary end point was 1-year EFS. Primary or secondary GR or death was
considered an event. Primary GR was defined as the presence of <20% donor cells as
assessed by bone marrow or peripheral blood chimerism assays (any lineage) on or
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after day 42. Secondary GR was defined as the presence of <20% donor-derived
hematopoietic cells in peripheral blood or bone marrow in a patient with prior
evidence of >20% donor cells. The level was chosen based on absence of SCD
symptoms, even when donor chimerism in blood or marrow approached 10%.21,25
Survival was defined as the time from transplant to death or last follow-up. Neutrophil
recovery was defined as the first of 3 days when the absolute neutrophil count was
0.5 109/L. Platelet recovery was defined as the first of 7 days without a platelet
transfusion that the platelet count was 50 109/L. Acute and chronic GVHD were
graded by Seattle (ie, limited/extensive) and National Institutes of Health criteria (ie,
mild/moderate/severe).26 Common Terminology Criteria for Adverse Events version
3.0 was used to report expected grade 3-5 adverse events. Major regimen-related
toxicity (RRT) was defined as grade 4 or 5 in any organ system or grade 3 for
pulmonary, cardiac, renal, central nervous system, oral, or mucosal.27 HRQL was
assessed pretransplant (within 2 months of transplant), and thereafter on day 100, at 6
months, and at 1 year posttransplant using the Child Health Questionnaire (CHQ).
The CHQ was chosen because it was the only HRQL measure that was validated and
reliable for use in children with SCD at the time the study commenced.28,29 The
CHQ-Parent Form 50 was used for parent reports, and the CHQ-Child Form 87 was
used for the child self-report for children aged 10 years.

Statistical analysis
The primary hypothesis was that a RIC regimen would be sufficient for stable
engraftment after HLA-matched URD BMT and result in 1-year EFS 75%. The
sample size of 30 patients was chosen based on a 95% confidence interval (CI) length
of 31. However, 1 patient was deemed ineligible after enrollment because the patient
and donor were mismatched at 2 HLA-loci. Therefore the analysis includes 29
patients.

EFS and overall survival were calculated using the Kaplan-Meier estimator.30 The cumulative
incidence method was used to estimate the incidence of events in the presence of competing risks
for neutrophil and platelet recovery and acute and chronic GVHD; in each case, death was
considered the competing risk.31 HRQL measurement was based on the CHQ Parent Form 50
(for patients 5-18 years old) and the CHQ Child Form 87 (for patients 10-18 years old). Mean
scores for the CHQ were calculated based on a 4- to 6-point response scale for each item and
transformed according to the developers instructions to a 0 to 100 scale, with a higher score
representing a better quality of life.32 One domain, Change in Health, is composed of 1 question
that is reported on a 1- to 5-point scale, with a higher number meaning better health. The impact
of a change by >1 point is considered significant on a 5-category scale.33,34 HRQL data were
analyzed for changes in mean HRQL score from pretransplant measurement and performed as an
exploratory analysis, given the small sample size. A paired Student t test was used to assess
changes from baseline to each posttransplant time point (day 100, 6 months, and 1 year). Only P
values of <.01 were considered significant for the HRQL analyses, given the multiple
 Qasba 9

comparisons. All analyses were performed using SAS version 9.3 (Cary, NC).

Results
Patient and donor characteristics
The characteristics of the donors and 29 patients who met eligibility criteria are shown in Table
2. All patients had a hemoglobin SS genotype. The median age at transplant was 14 years (range,
6-19 range), and 55% were male. Indications for transplant included stroke (41%), elevated
transcranial Doppler velocity (7%), recurrent episodes of acute chest syndrome (14%), or
significant pain (41%). Pretransplant, 26 patients had performance scores of 90 or 100, 2 patients
had a score of 80, and the remaining patient had a score of 70. All patients had received
erythrocyte transfusions before transplant. The median serum ferritin level was 722 ng/mL
(range, 55-7324 ng/mL). Eight patients underwent liver biopsy for history of chronic red cell
transfusions and a serum ferritin level of >1000 ng/mL, but no patient was excluded because
none had evidence of bridging fibrosis or liver cirrhosis. The median hemoglobin S at transplant
was 20.8% (range, 3.9%-43%). All 29 eligible patients received bone marrow grafts from an
adult URD and were HLA matched at the allele-level at HLA-A, -B, -C, and -DRB1. One
unrelated adult donor was a carrier with hemoglobin AS genotype. The median total nucleated
cell dose of the bone marrow graft was 3.5 108/kg (range, 1.3 108/kg to 6.8 108/kg). The
median CD34 dose of the graft was 2.9 106/kg (range, 0.3 106/kg to 9.2 106/kg).

Donor, recipient, and transplant characteristics

EFS, overall survival, and engraftment
The primary end point was met. The 1-year EFS was 76% (95% CI, 56-88) and the 1-year
overall survival was 86% (95% CI, 67-95). At data cutoff in March 2016, the 2-year EFS was
69% (95% CI, 48-82) and the 2-year overall survival was 79% (95% CI, 59-90) (Figure 1).
Twenty-seven of 29 patients engrafted. The median time to neutrophil recovery was 12 days
(range, 6-16 days) and the median time to platelet recovery was 24 days (range, 7-90 days),
similar to published results using URDs.35 Two patients experienced primary GR (day 39 and
day 91); 1 patient developed secondary GR on day 48 for a cumulative incidence of GR of 10%.
All 3 patients experiencing GR recovered host hematopoiesis without marrow aplasia. Because
mixed chimerism occurs frequently after transplant for SCD, we evaluated the percentage of
donor cells at 3 months, at 1 year, and at 2 years.20,21,25 All engrafted patients demonstrated
>90% donor chimerism at 3 months, and this persisted at the 1-year and 2-year time points in
evaluable patients (n = 22 and n = 19 at 1 and 2 years, respectively). Hemoglobin S levels were
undetectable in all but 1 patient who received a graft from an URD with sickle cell trait, and the
hemoglobin S level was consequently 42%.

Although a RIC regimen was administered, RRT was implicated in 83% of grade 3-5 adverse
events (63/76). Ten patients developed PRES with a 1-year incidence of 34% (95% CI, 18-52),
resulting in reiteration of the importance of strict blood pressure control based on lower blood
pressure norms established for SCD patients and of correcting any electrolyte imbalance. Two
 Qasba 10

PRES events occurred before transplant. In the remaining 8 patients, calcineurin inhibitor was
withdrawn. Thereafter, 1 patient received sirolimus, 2 received mycophenolate mofetil, and 5
received no alternate GVHD prophylaxis. Three patients developed renal failure and required
dialysis. These events were transient, and all patients fully recovered.

Eight patients died after transplant. Seven patients, all aged 14 years, died of GVHD
and related complications (Table 3). Five of the 7 patients had ferritin levels >1000
ng/mL, although none had fibrosis or cirrhosis. One patient with primary GR died of
infection 3 months after a second myeloablative transplant. Four GVHD-related
deaths occurred within the first year after transplant, whereas 3 occurred between 507
and 960 days.

Cause of death in 7 patients

GVHD

The cumulative incidence on day 100 of grade II-IV acute GVHD was 28% (95% CI, 13-45),
and was 17% (95% CI, 6-33) for grade III-IV acute GVHD (Figure 2A). The cumulative
incidence of chronic GVHD at 1 year (Figure 2B) was 62% (95% CI, 41-77), with 38%
classified as extensive. By National Institutes of Health scoring criteria, chronic GVHD was
classified as mild in 6 patients, moderate in 8, and severe in 5. Of the 19 patients with sustained
donor engraftment, 4 discontinued immune suppression by 1 year, 6 discontinued in the second
year, and 5 discontinued after 2 years. Of the remaining 4 patients, 1 was weaning immune
suppression when lost to follow-up at 1 year, 2 were weaning post-GVHD resolution, and 1
continued treatment of stable chronic GVHD. Performance scores at the 2-year or last follow-up
visit were 100 in 13 patients, 90 in 5 patients, and 80 in 3 patients.

Figure 2. Probability of GVHD. The 100-day probability of acute GVHD (A) and the 1-year
probability of GVHD (B) after URD transplant for severe SCD.
HRQL
SCD adversely affects quality of life, as previously reported.36 We were interested in
learning whether HRQL improved after URD BMT in pediatric recipients. Validated
measures for HRQL include change in health, physical functioning, behavior, and self-
esteem. Parental proxies and patients who completed the forms, as indicated based on
age, reported significant improvements in the change in health domain
posttransplant (Table 4). Although initially, patients did not report any differences,
parent proxies (n = 21) reported significantly worse Self-Esteem HRQL scores (mean
change, 15.12; P = .006) but significantly better General Health Perception scores
(mean change, 11.13; P = .0003) at day 100 compared with pretransplant baseline. The
child-reported Change in Health score (n = 13) improved by a mean of 1.46 (P = .0013)
 Qasba 11

at 12 months posttransplant compared with pretransplant scores. Parental proxies

reported similar improvements at 6 and 12 months compared with pretransplant
scores (mean change, 1.15 and 1.53, respectively; P < .01). The limited sample size
precluded subanalyses such as assessing these changes in patients with and without
chronic GVHD (see supplemental Table 1, available on the Blood Web site).

HRQL changes from pretransplant baseline to day 100, 6 months, and 1 year
Discussion
Although EFS after HLA-matched sibling donor transplant is >90%, most patients do not have
an HLA-matched sibling.4,5,21,37,38 This is the first multicenter URD transplant trial for SCD
in North America and was conducted to expand access to transplantation utilizing HLA-matched
URDs. The RIC regimen of alemtuzumab, melphalan, and fludarabine was used to overcome the
higher risk of GR with URD BMT while limiting the toxicities associated with myeloablative
regimens that may be exacerbated in patients with severe SCD and may limit patient
acceptance.14,16,39,40

Although the trial met the prespecified 1-year end point of 75% EFS, the 1-year chronic GVHD
rate was higher than expected after HLA-matched URD BMT, and GVHD was the predominant
cause of death, noted primarily in older patients. Reports in African Americans with severe
aplastic anemia (combining sibling and URD transplants) suggest an overall chronic GVHD rate
of 36% (95% CI, 24-48) compared with 30% noted in whites (P = .36), although extensive
chronic GVHD was observed more commonly in African Americans than in whites (72% vs
49%; P = .06), as was GVHD-related mortality.41 Other than race, additional factors may have
influenced the observed high rates of chronic GVHD in this trial. HLA matching at HLA-DPB1
loci was not considered in donor selection, and a mismatch at this locus increases the risk of
acute GVHD.42-44 Another plausible explanation could be the timing of alemtuzumab
administration 3 weeks before infusion of the graft (distal administration) to overcome host
rejection of the graft. It was timed to achieve low alemtuzumab levels at the time of graft
infusion to maximize donor T-cell engraftment, and thus did not have a significant effect as a
GVHD prophylaxis agent.21 Chronic GVHD rates are also expected to be higher in URD BMT
and increase with recipient age; the higher rates observed in this trial are consistent with less
protection against chronic GVHD.45-47 Further, the protocol recommended calcineurin
inhibitor taper early (after day 100) in the absence of GVHD and may have contributed to de
novo chronic GVHD subsequently. Chronic GVHD developed in 8 of 10 patients after they
developed PRES symptoms. The protocol did not specify alternate GVHD prophylaxis in the
event of PRES, and treatment was left to the centers choice. Because it is common practice to
discontinue or modify calcineurin inhibitor use after PRES, it is possible that the withdrawal or
modification of the calcineurin inhibitor after the development of PRES may have additionally
contributed to GVHD. Alemtuzumab or anti-human T-lymphocyte immune globulin used just
proximal to transplant can offer better protection against GVHD but predisposes to mixed
chimerism and rejection.48-50 Novel preparative agents such as treosulfan and GVHD
prophylaxis methods such as posttransplant cyclophosphamide have shown recent promise in
transplantation for SCD.51,52
 Qasba 12

HRQL improved significantly by 1 year posttransplant in the areas of Change in Health for these
patients compared with pretransplant scores. Other HRQL domains did not show significant
changes from baseline. The significant changes noted here, even in this small sample size,
support that these children felt better and reported better functioning overall related to their
health after transplant, despite the high incidence of chronic GVHD. We would expect patients
with significant chronic GVHD after BMT to experience lower HRQL than those without, but
the sample size was too small for a meaningful comparison between the two groups.

No patient developed hepatic sinusoidal syndrome or idiopathic pulmonary syndrome. However,

one-third of the patients developed PRES (a known complication of SCD and hemoglobinopathy
transplants) that was reversible, despite our recommendation for strict blood pressure monitoring
and prompt intervention.53,54 Baseline blood pressure in SCD patients is generally lower than
published norms for age, race, and sex, and the use of corticosteroid and calcineurin inhibitors
may have exacerbated this complication. 53,55-57

In conclusion, the trial met its prespecified 1-year EFS, and significantly improved HRQL was
reported posttransplant. However, although the RIC provided successful engraftment in the
majority of patients, the regimen cannot be considered safe for widespread adoption without
modification due to the RRT and high rate of chronic GVHD, which was the predominant cause
of mortality. Future trials on URD transplantation for SCD should focus on strategies that
minimize risks of GVHD and include stopping rules for chronic GVHD
 Qasba 13

Source 3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908942/
Background
Antibiotic prophylaxis is a mainstay in sickle cell disease management. However, adherence is
estimated at only 66%. This study aimed to develop and validate a Sickle Cell Antibiotic
Adherence Level Evaluation (SCAALE) to promote systematic and detailed adherence
evaluation.

Methods
A 28-item questionnaire was created, covering seven adherence areas. General Adherence
Ratings from the parent and one health care provider and medication possession ratios were
obtained as validation measures.

Results
Internal consistency was very good to excellent for the total SCAALE (=0.89) and four of the
seven subscales. Correlations between SCAALE scores and validation measures were strong for
the total SCAALE and five of the seven subscales.

Conclusion
The SCAALE provides a detailed, quantitative, multidimensional, and global measurement of
adherence and can promote clinical care and research.

Keywords: penicillin prophylaxis, SCAALE, newborn screening program, Sickle SAFE

Program, hemoglobinopathy, compliance

Background
Children with sickle cell disease (SCD) have compromised splenic function that increases the
rate of bacteremia with the ensuing risk of rapid progression to sepsis, septic shock, and
death.1,2 Penicillin prophylaxis has become a mainstay in the management of children with SCD
to prevent complications relating to infection.3 With the implementation of prophylactic
antibiotic prescribing, the risk of bacteremia in febrile children with SCD has decreased from
3%5%, as documented from 1975 to 2002,410 to <1%.2,11

Yet, in spite of penicillins effectiveness, adherence to the twice-daily treatment regimen is of

enduring concern.1222 Low adherence rates illustrate the need for an ongoing and systematic
 Qasba 14

method to measure and understand adherence in this community with the goal of improving
treatment outcomes. Even a low incidence rate can affect a numerically large group of children
when a disorder is as prevalent as SCD,23,24 and rates of bacteremia as a result of nonadherence
may be higher in certain high-risk subpopulations affected by SCD. Therefore, measurement and
improvement of adherence offers the potential for documenting, understanding, and improving
outcomes in high-risk subpopulations and further reducing the number of bacteremia cases
associated with SCD.

Several methods have been used to measure adherence in SCD. These include medical record
reviews,20 urinalysis,13,14,17,20 self-/parent-report by questionnaires, interviews, or visual
analog scales,14,18,20,25 parent/proxy Morisky scores,25 medical provider reports,25 clinic
visit attendance,25 medication event monitoring system (MEMS) pill bottles,15 and medication
possession ratios (MPRs) using pharmacy claims12,16,22,26 or dispensation data.19,21,25 Most
of these measures have been validated in other clinical populations; yet, the information we can
glean from them is limited. As Beverung et al,12 who utilized an MPR, stated, [] we cannot
explain why adherence is low []. The MPR, for instance, produces an adherence rating, but
does not provide information on (potentially modifiable) variables underlying nonadherence.
Also, MEMS and MPRs do not provide information about whether the medicine was actually
given to the child or under what conditions. Furthermore, medical record reviews, urinalysis,
MEMS, and MPRs are costly and time-intensive to obtain, reducing their feasibility for daily
clinical use at a population level.

Furthermore, although several self- or parent-report scales have been used to measure the factors
associated with antibiotic nonadherence worldwide,27 most have been used as outcome
measures in assessment or treatment studies without extensive psychometric analysis to support
their reliability and validity. One antibiotic adherence parent-report scale that has been
extensively validated is the Parental Perception on Antibiotics scale, which was originally
developed to investigate the factors related to antibiotic overuse in Saudi Arabia.28 The Parental
Perception on Antibiotics scale has demonstrated good internal consistency, good face and
construct validity, and good discriminant and convergent validity in parents, in particular.2830
However, it was not developed for the unique cultural and situational aspects of care and
treatment of the child with SCD.

The lack of an economically and clinically feasible instrument to measure penicillin prophylaxis
adherence in SCD has resulted in almost no systematic, population-wide documentation or
monitoring of adherence in daily clinical practice, despite the well-established value of penicillin
prophylaxis for preventing infection in this at-risk population. This critical gap in our
understanding of adherence to penicillin prophylaxis (and application of adherence knowledge to
the daily clinical setting) exposes a need in SCD clinical management and research for a more
feasible, clinically relevant, multidimensional measure of adherence, that is, one that has more
layers of information than just a single, global score.
 Qasba 15

In light of the need for and potential benefit of a new multidimensional measure of adherence
that is valid, of low cost, and provides real-time information based on the perspective of the
individual most responsible for adherence (the caregiver), we developed and validated the Sickle
Cell Antibiotic Adherence Level Evaluation (SCAALE) (Supplementary material). This study
aimed to describe the psychometric properties and validity of the SCAALE and demonstrate its
potential utility as a clinical and research instrument. Developed using a conceptual framework
of adherence first utilized in hemophilia,31,32 the SCAALE is a brief parent/guardian-report
questionnaire designed to evaluate specific areas of adherence, identified as subscales, as well as
global adherence to antibiotic prophylaxis.

Methods
Recruitment and procedures
The study protocol was approved by the St Vincent Hospital Institutional Review Board. Patients
were recruited by Sickle SAFE (Screening, Assessment, Follow-up, and Education) Program
coordinators during home visits or by telephone. All participants provided informed consent;
parents/guardians consented for minor children. Participants also signed a release of information,
granting permission to contact the patients pharmacy and obtain dispensation records for the
year preceding questionnaire completion. The parent/guardian was then given the SCAALE with
a demographic cover sheet and allowed as much time as necessary to complete the survey.

Participants
Participants were recruited from the population of patients enrolled in the Sickle SAFE Program,
the Indiana State Department of Health-supported hemoglobinopathy newborn screening (NBS)
follow-up program. This program ensures timely notification of affected patients, educates
families about the confirmed diagnosis and management of the disease, and links families to a
hematologist. All infants in Indiana identified by the NBS laboratory as having a
hemoglobinopathy are enrolled in the Sickle SAFE Program. From that population, we recruited
only patients diagnosed with hemoglobin SS disease (Hb SS), S beta thalassemia+ (Hb S/+ Th),
S beta thalassemia0 (Hb S/0 Th), or hemoglobin SC disease (Hb SC) who had been prescribed
twice-daily antibiotic prophylaxis for at least 3 months (the recall period on the questionnaire).
The study was limited to English-speaking patients under 6 years of age.

Measure
The SCAALE is a 28-question survey divided into seven (four-question) subscales
(Supplementary materials for SCAALE items):

Time: Does the patient take the antibiotic on the prescribed days and at the prescribed times?
 Qasba 16

Dose: Does the child receive the appropriate dose of antibiotic? Do issues related to difficulty
swallowing, misbehavior, or trouble measuring interfere with appropriate dosing?
Pharmacy: Do pharmacy-related barriers, such as hours of operation and dispensation errors,
limit patient adherence?
Plan: Does the patient plan appropriately to have an adequate supply of antibiotic to be able to
adhere to the regimen?
Remember: Do issues of forgetfulness impact the patients adherence?
Communicate: Does the patient communicate with the childs physician at appropriate times,
such as when there are questions about the antibiotic regimen or when fever >101F occurs?
Environment: Are there environmental factors, such as financial or transportation barriers,
stress, and chaos, or lack of support that contribute to nonadherence?
An eighth (five-question) subscale, Other Caretakers, with questions about other caretakers
responsible for administering the antibiotic and the effect of this on adherence, was piloted based
on input from the patient focus group. It remains under further review and is excluded from this
report.

Questions and subscales were rationally developed and revised in a five-step process to optimize
content validity: 1) initial question development by hemoglobinopathy care specialists; 2)
question review by a parent/guardian focus group; 3) question revision and addition of two
subscales (Pharmacy and Other Caretakers) based on focus group feedback; 4) SCAALE
administration to a 34-patient pilot sample for preliminary reliability and validity analysis; and 5)
based on pilot sample results, slight modifications to some questions and to descriptive anchors
for the scoring scale to improve sensitivity. Questions were written to reflect the caretakers
actions and experiences managing a twice-daily antibiotic schedule.

SCAALE response options are scored on five-point Likert scales (Always, Almost Always,
Often, Sometimes, Rarely or Never). An answer of Always reflects the best possible
adherence for some questions and the worst possible adherence for others. Questions are
scored in such a way that responses indicating worst adherence receive one point while
responses indicating best adherence receive five points. SCAALE subscale and total scores are
the averages of the questions comprising them and range from 1 (least adherent) to 5 (most
adherent). The survey asks the respondent to report adherence for the past 3 months.

Validation measures of adherence

Three adherence measures were used to demonstrate SCAALE construct validity: General
Adherence Rating (GAR) by parent, GAR by health care provider, and MPR (see descriptions
later). Because no single adherence measure can provide a perfect characterization of adherence
 Qasba 17

(short of a behavior coder who directly observes the child constantly), an adherence measures
validity is best captured by demonstrating significant relations between the adherence measure
and several other estimates of adherence.

General Adherence Rating

The demographic cover sheet included a GAR scale on which respondents rated their global
adherence level using a scale of 1 (rarely or never follows the doctors instructions for
antibiotic use) to 10 (always follows the doctors instructions for antibiotic use). The parent
completing the SCAALE and one health care provider per subject provided a GAR.

The health care provider completing the GAR was the individual who most closely follows the
patients prophylactic antibiotic treatment for SCD. Provider responses were based on a global
impression of the familys adherence. Similar provider-rated global impression scales are widely
used in medicine, including visual analog scales33 and global impression ratings.34

The GAR has been validated in previous adherence research.31,32

Medication possession ratio

The MPR is a widely used adherence measure and has been used in several studies evaluating
antibiotic adherence in SCD.12,16,19,21,22 Advantages of the MPR are that it does not rely on
self-report and the data can be obtained from known sources. However, limitations exist.
Refilling a prescription is not the same as ingesting it, and MPR is best calculated in a closed
pharmacy system,35 which was not available for this study.

An MPR for the 3 months preceding SCAALE completion was calculated using pharmacy
dispensation records. The MPR was the ratio of the number of days during which the patient had
antibiotics as indicated by the number of doses dispensed (numerator) to the number of days in
the study period (90 days, denominator). An MPR of 1.0 indicates 100% adherence in terms of
prescription refills relative to medication prescribed, while lower MPRs indicate that less
medication was dispensed than was prescribed (lower adherence). In some cases, MPRs >1.0
were observed. To reflect that MPRs >1.0 did not necessarily indicate greater adherence than
MPRs =1.0, MPR values >1.0 were recoded as 1.0.

Statistical analysis

The SCAALE development process followed standardized methodology and a protocol utilizing
commonly accepted statistics for validation studies.36,37 The statistics reported are outlined
 Qasba 18

later.

Descriptive statistics for SCAALE item, subscale, and total scores

Descriptive statistics and distributions (mean, range, standard deviation [SD]) of SCAALE total
and all subscale scores are provided. Because most subjects report adherence to a medical
regimen, it is not uncommon for scores to cluster at the upper end of the distribution.31,32 A
very significant clustering of scores at the upper end of the distribution represents a ceiling
effect. For SCAALE scores, ceiling effects were defined as either 90% of the answers on any
question being the highest possible option (ie, 5) or SD <0.5 and mean >4.8, which would
indicate restricted variance.

Subscale intercorrelations
Subscale intercorrelations were calculated to investigate relations among the different
areas of adherence measured by SCAALE subscales. Strong subscale intercorrelations
demonstrate convergent validity, by showing the subscales measure the same
construct. Intercorrelations are reported as Pearson product-moment correlation
coefficients (r), which range from 1.0 to +1.0; values closer to 0 reflect weaker
relationships.

Internal consistency reliability

Internal consistency reliability (ICR) is a measure of whether a group of
questions evaluate the same defined concept. This was assessed for the total
SCAALE and all subscales and is reported as Cronbachs alpha (). This
statistic ranges from 0.0 to 1.0; the closer to 1.0, the stronger the ICR. Given
the short subscale length (four questions), making higher more difficult to
achieve, 0.8 was considered to reflect excellent ICR; =0.70.79, very
good; =0.60.69, good; and =0.50.59, minimally acceptable.

Correlations with validity measures

A valid SCAALE must accurately reflect adherence, shown by shared variance with other
estimates of adherence. One test of this is a correlation between the scale score and the validity
measure (either GAR or MPR). Correlations with validity measures are reported as Pearson
product-moment correlation coefficients (r) and associated P-values.

Results
Demographics
Eighty-eight families were recruited; 21 declined, primarily due to lack of interest in the study or
 Qasba 19

a desire for privacy. An additional seven, who were consented by telephone, did not return
mailed questionnaires. Of the 60 remaining, two participants were excluded due to age being >6
years. This resulted in a sample size of 58. See Table 1 for sample demographic and medical
information.

Question- and subscale-level descriptive data and intercorrelations

At a question level, significant ceiling effects were found for 9/28 questions (three questions
each from the Dose, Pharmacy, and Environment subscales). All score distributions were
skewed negatively, that is, most data were at the high end of the distribution. Item-level data are
available in Table S1.

Mean total SCAALE score was 4.7, with a range of 3.145.00 (Table 2). Subscale mean scores
ranged from 4.4 (Plan) to 4.9 (Dose and Environment). The Time, Plan, and
Environment subscales had the highest median intercorrelations with the other six subscales
(0.53, 0.43, and 0.40, respectively), whereas the Pharmacy (0.33) and Communicate (0.14)
subscales had the lowest median intercorrelations. The SCAALE total score was significantly
correlated with all subscales (median correlation =0.64, range =0.50 [Communicate] to 0.87
[Plan]; a table of all intercorrelations is available from the authors).

Internal consistency reliability

ICR for the total scale was excellent at =0.89 (Table 2). Subscale ICRs were variable, ranging
from excellent 0.86 (Time), 0.83 (Communicate), and 0.82 (Plan); to very good 0.77
(Remember); to poor 0.22 (Environment), 0.24 (Pharmacy), and 0.32 (Dose). Notably, subscales
with poor ICR are also those containing the most significant ceiling effects.

Validity adherence measures

Consistent with SCAALE question and subcale ratings, GAR measures were significantly
negatively skewed (ie, toward the high end of the distribution). Fifty-seven (98%) parents
provided GARs, with 89% rating their adherence 9 or 10 (mean 9.5, SD 1.05). Health care
provider GARs were given for 33 (56%) participants, with 61% receiving a score of 9 or 10
(mean 8.8, SD 1.25). Health care providers included primary care providers (PCPs) (n=22, 23
subjects), hematologists (n=4, six subjects), and PCP with a focus on hematology (n=1, four
subjects). Parent GAR correlated significantly with provider GAR (0.48, P<0.01).

MPRs were calculated for the 37 (64%) participants for whom pharmacy dispensation data were
available. MPR ranged from 0.11 to 1.00 (mean 0.65, SD 0.30). Only 38% of the sample had
MPRs >0.80, while 19% of the sample had MPRs of 0.33 or less. MPR correlated significantly
with provider GAR (r=0.57, P<0.02), but not with parent GAR (r=0.24, P<0.15).
 Qasba 20

The SCAALE total score correlated significantly with parent GAR (r=0.69, P<0.01), provider
GAR (r=0.44, P<0.05), and MPR (r=0.46, P<0.01). The majority of SCAALE subscales also
correlated significantly with two or more of the validity measures, and the Plan subscale
correlated significantly with all three validity measures. All SCAALE subscales with the
exception of Pharmacy and Communicate correlated significantly with Parent GAR.
Provider GARs were significantly correlated with the Dose and Plan subscales, and
correlations between Provider GAR and the Time and Communicate subscales were high
(P<0.06). Time, Plan, and Environment were significantly correlated with MPR (Table 3).

Discussion
Daily oral administration of prophylactic penicillin has significantly reduced mortality associated
with bacterial infections in children with SCD.2,11,38 This treatment is recommended by the
National Heart, Lung, and Blood Institute39 as a standard of care for children with Hb SS and
Hb S/0 Th under 5 years of age and in older children who have had a previous severe
pneumococcal infection or have functional/surgical asplenia. It was also identified in 2011 by a
Sickle Cell Disease Expert Panel as a quality of care indicator rated 9 out of a possible 10 for
importance.40 However, in spite of these endorsements, the effectiveness of antibiotic
prophylaxis for young children with SCD may be limited by nonadherence to the treatment
recommendations of twice-daily administration. There does not currently exist a widely
accepted, validated, clinically useful means specifically designed to measure the multiple
dimensions of prophylactic antibiotic adherence in SCD. This study aimed to address this gap by
developing and validating a standard measure of global and specific dimensions of prophylactic
antibiotic adherence in SCD: the SCAALE.

In addition to providing a global view of adherence based on a total score, the SCAALE contains
seven subscales that yield more specific and detailed descriptions of different aspects of
adherence. Based on prior empirical research31,32 and focus group data, adherence is not a
simple unitary construct, but rather consists of, and is driven by, multiple related factors such as
timing, dosing, planning, and access to medical care. Therefore, measuring the dimensions of
adherence in addition to a total score is important for understanding the underlying contributors
and components of nonadherence, providing a first step toward targeted interventions for at-risk
families.

The complete 28-item SCAALE total score has both the strongest ICR and the strongest validity
correlations with global measures of adherence as rated by parents, providers, and MPR. This is
not surprising as the SCAALE total score captures all dimensions of adherence in a single
measure, whereas subscales focus on specific areas of adherence that may be more important in
some families and less important in others. Also, the SCAALE total score has a broader
distribution and larger variance than the subscales because it consists of more items across
multiple adherence areas. Finally, longer scales generally have larger ICR values than shorter
scales because Cronbachs is partially dependent on the length of the scale.36
 Qasba 21

Reliability and validity of the subscales were variable, with some subscales showing strong ICR
and validity (Time, Plan, Remember, and Communicate) and others showing
questionable ICR but significant validity correlations (Dose and Environment). The
Pharmacy subscale, on the other hand, had poor ICR and low validity correlations, suggesting
a need for additional research. The Pharmacy subscale is nevertheless recommended for
inclusion in the SCAALE because of its content validity based on unanimous recommendation
by focus group participants and experts in SCD pediatric clinical practice.

Parents and providers rated the study sample as highly adherent, as measured by GARs and the
SCAALE. Studies utilizing urinalysis as an adherence measure have found that parents tend to
self-report a higher level of adherence than is reflected in urinalysis.14,17,20 Thus, it is possible
that the parents GAR was somewhat inflated. However, demographic and clinical care variables
support a high level of adherence in this population. Although such high adherence ratings are
desirable from a clinical perspective, they limit the power of psychometric analyses by
introducing restricted range and ceiling effects into the analysis. As noted under ICR, subscales
with near-ceiling effects (Dose, Pharmacy, Environment) had low ICR, likely reflecting
insufficient variability in the sample data as opposed to poor quality of the subscales a larger
sample and further validation analysis are needed to address this question. Subscales with greater
variability (Time, Plan, Remember, Communicate) had good-to-excellent ICR.

Of the subscales, Plan and Time were most consistently and significantly related to the three
validity measures. This suggests that across the entire sample, behaviors related to planning to
have antibiotics available and administering them at the proper time are especially important for
global adherence, and therefore should be core components of adherence measurement and
intervention in this population.

Our overall findings lend themselves to several implications and recommendations. The total
scale score was the most reliable, valid, and best index of global adherence, reflecting its
integration of multiple dimensions of adherence. It showed very strong ICR and correlations of
0.44 or higher with parent GAR, provider GAR, and MPR. GAR scores provided by the parent
did not correlate significantly with MPR (r=0.24, P=0.14), while SCAALE total scores based on
parent-report did correlate significantly with MPR (r=0.46, P=0.004). This finding indicates that
measuring global adherence based on a sum of the specific domains evaluated by the SCAALE
is superior to obtaining a single global estimate provided by the parent. Such a finding also
demonstrates that the core domains of the SCAALE reflect critical adherence components related
to MPRs.

Our approach to SCAALE validation emphasized its relationships with multiple other methods
of estimating adherence, each of which has advantages and limitations. None of the validating
measures used in this study is without limitations, nor do we claim that the SCAALE is a perfect
 Qasba 22

method for determining adherence. Rather, parent-report of adherence has specific advantages
and contributions to estimating adherence that cannot be obtained with other methods such as
MPR or GAR. Furthermore, if adherence interventions are to target parents, it is critical to
understand the components and barriers to adherence based on their report. As a result, the
SCAALE has a significant and important role as a parent-report measure of adherence to
penicillin prophylaxis. We took a multisource (parent-report vs provider-report), multimethod
(questionnaire and prescription record) approach to obtaining other validity measures of
adherence for the SCAALE, demonstrating significant relationships among adherence estimates
based on different methods and sources.

Although health care provider ratings of adherence have limitations, they are correlated (albeit
modestly) with methods of estimating adherence. For instance, Logan et al41 found significant
relationships between provider-reported estimates of adherence and patient adherence to different
domains measured using the Illness Management Survey. Zeller et al42 found a significant
correlation between the physicians predictions of adherence and MEMS measures of adherence.
Because health care providers see a wide range of patients, they may be able to detect extremes
in adherence at above chance levels, and their perspective on adherence is valuable since it is
likely to influence their medical decision making and interactions with patients.43

Importantly, the high level of adherence in our sample may, in part, reflect the degree of
resources devoted to this patient group, which is actively monitored, managed, and supported by
a structured NBS follow-up program. Upon receiving an abnormal hemoglobin result from the
NBS laboratory, a Sickle SAFE Program coordinator contacts parents by telephone to discuss the
diagnosis and schedule a home visit. The coordinator also contacts the PCP to provide education
on the importance of antibiotic prophylaxis and ensure the first prescription for antibiotic
prophylaxis is written. At the first home visit, when the patient is ~36 weeks of age, the
coordinator delivers the first 3 months supply of penicillin, provided free of charge. During the
same home visit, the coordinator provides education and training on antibiotic reconstitution and
dose administration. Sickle SAFE participants receive regular communications from the
coordinator and a direct line remains open for the participants to contact the Program staff, which
includes the coordinator and a pediatric hematologist. Moreover, if a participant loses insurance
coverage, the Sickle SAFE Program provides penicillin for the uninsured period at no cost to
ensure continuity of care. Research has shown that such patient-centered interactions promote
adherence and lead to improved health outcomes.44 It is quite possible that lower levels of
adherence would be reported in samples of patients who do not receive this level of support.

Some methodological considerations should be taken into account when interpreting results of
this study. First, although the sample size of 58 was sufficient for psychometric analysis, a larger
sample would likely yield greater variability among scores and may result in stronger reliability
and validity statistics. It is possible that some of the weaker reliability statistics were a result of
insufficient variability.
 Qasba 23

A second consideration is the skewed distribution of SCAALE scores. We believe that this
reflects the tendency of this particular sample to be adherent due to frequent patient-centered
interactions with the Sickle SAFE Program coordinator. While this may be a positive reflection
on that program, a less-adherent sample could produce stronger reliability and validity
correlations by providing a larger range of scores and wider distribution within the range.
Similarly, of those patients enrolled in the Sickle SAFE Program, it is possible that only the most
adherent chose to participate, introducing selection bias.

A third methodological consideration is the quality of the pharmacy dispensation data available
for calculating MPRs. In spite of multiple telephone follow-ups to patients pharmacies,
dispensation records were available for only 37 (64%) study participants. Of the data obtained,
we were unable to differentiate instances of missing data (due to pharmacy error or the failure to
provide a comprehensive list of pharmacies) from when patients were actually missing
dispensations (due to nonadherence). To be as thorough as possible, when data were missing, a
second attempt was made to gather the data by going back to the patient and pharmacy to check
for errors in record provision or pharmacy telephone numbers.

In order to better understand group differences between subjects who did and did not have
available MPR data, we compared demographic and adherence characteristics of the 21 subjects
with no MPR data with demographic and adherence characteristics of the 37 subjects who
provided MPR data. The results showed no difference in age (t (56)=1.38, P=0.174) or sex (2
(1)=0.001, P=1.00) between the groups. However, children with MPRs had higher adherence as
rated on the SCAALE total score (t (56)=2.16, P=0.035) and parent GAR (t (55)=3.17, P=0.002),
compared to those for whom we were unable to obtain MPRs (Table S1). The groups did not
differ on provider GAR (t (31)=1.20, P=0.028). These differences may reflect the fact that
subjects with greater adherence live in more organized, structured, and predictable settings,
which are more consistent in their use of pharmacies and, therefore, could provide more accurate
data for us to use in accessing pharmacy records. As a result, MPR data may have
overrepresented subjects with good adherence, although there was sufficient variability in MPR
scores to allow for significant correlations with other adherence measures. The
overrepresentation of good adherence in MPR data would restrict the range of adherence and
may have reduced the correlations between MPR and other adherence ratings. Therefore, MPR
data in a less-adherent sample may produce higher correlations and stronger validity results; this
should be investigated in future research.

A fourth consideration in the interpretation of the SCAALE is the rating method, which is based
on parent-report. Parent-reports are susceptible to bias and error ranging from social desirability
to denial to poor self-awareness and self-monitoring. Furthermore, significant correlations
between SCAALE scores and Parent GARs may be influenced by method bias because both
were completed by the same rater. For this reason, we obtained adherence validity scores from
three critical perspectives: parent, provider, and pharmacy dispensation data. Importantly,
SCAALE total scores correlated with all three types of validity measures, demonstrating that
method bias from parent-report does not account for the validity results.
 Qasba 24

While the SCAALE demonstrates strong psychometric properties and fills a critical unmet need,
additional research is needed to address some shortcomings. Additional planned scale
development initiatives are a testretest stability investigation and use of the SCAALE with a
large, diverse group of treatment centers with varying NBS follow-up programs. Future research
may also investigate relations between the SCAALE and other validation measures such as
urinalysis, as well as validity of the SCAALE in non-English speaking samples from other
countries. Also, a study is planned to evaluate hydroxyurea adherence using a similar parent-
report methodological approach and including MEMS devices for scale validation, which, in
spite of their own limitations, are considered by some to be the gold standard in adherence
measurement.45

Conclusion
The SCAALE provides the first detailed, quantitative, dimensional, and global measurement of
adherence to antibiotic prophylaxis in SCD. Evidence from this study supports the reliability and
validity of the overall 28-question scale and of most subscales. Development of this scale
represents an important contribution to pediatric SCD with clear applicability to clinical
management, research programs, and state-funded NBS initiatives.
 Qasba 25

Sources 1 & 2 are not available online. I will bring them in on Monday.