Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: J Pediatr Health Care. 2020 Jun 5;34(5):424–434. doi: 10.1016/j.pedhc.2020.04.007

Vitamin D Supplementation Improves Health Related Quality of Life and Physical Performance in Children with Sickle Cell Disease and in Healthy Children

Kelly A Dougherty 1, Joan I Schall 2, Chiara Bertolaso 3, Kim Smith-Whitley 4, Virginia A Stallings 5
PMCID: PMC7483775  NIHMSID: NIHMS1587420  PMID: 32507538

Abstract

Introduction:

No study determined if vitamin D supplementation improves health-related quality of life (HRQL) using pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) or physical functioning in type SS sickle cell disease (HbSS).

Methods:

Subjects (HbSS(n=21) vs. healthy(n=23) randomized to oral daily doses (4000vs.7000IU) of cholecalciferol (vitamin D3) and evaluated 6 and 12 weeks for changes in serum 25 hydroxyvitamin D (25(OH)D), HRQL and physical functioning.

Results:

In HbSS, significant reductions in pain, fatigue and depressive symptoms and improved upper-extremity function were observed. In healthy, significant reductions in fatigue and improved upper-extremity function were shown. Significant improvements in peak power and dorsiflexion isometric maximal voluntary contraction (MVC) torques were observed in both groups. In HbSS, improved plantar flexion isometric MVC torques were shown. Both groups improved significantly in total BOTMP score.

Discussion:

Daily high-dose vitamin D supplementation for African American children with and without HbSS improved HRQL and physical performance.

Keywords: Sickle cell disease, vitamin D supplementation, quality of life, muscle strength, physical performance

Introduction

Sickle cell disease (SCD) has a detrimental impact upon health-related quality of life (HRQL) (Dale, Cochran, Roy, Jernigan, & Buchanan, 2011; Panepinto & Bonner, 2012; Panepinto, O’Mahar, DeBaun, Loberiza, & Scott, 2005; Wrotniak, Schall, Brault, Balmer, & Stallings, 2014). Furthermore, compared with healthy similarly aged children, deficits in muscle strength, function and physical performance in SCD have been reported (Dougherty, Bertolaso, Schall, Smith-Whitley, & Stallings, 2018; Dougherty, Schall, Rovner, Stallings, & Zemel, 2011). Suboptimal vitamin D status has been shown to be prevalent in children with SCD, and associated with poorer growth and disease outcomes (Adegoke, Oyelami, Adekile, & Figueiredo, 2017; Dougherty, Bertolaso, Schall, Smith-Whitley, & Stallings, 2015; Gregoire-Pelchat et al., 2018; Han et al., 2018; McCaskill, Ogunsakin, Hottor, Harville, & Kruse-Jarres, 2018; Osunkwo et al., 2011), however there have been few studies of the efficacy and safety of vitamin D supplementation in SCD that have been of sufficient size or quality to inform clinical practice (Soe et al., 2017).

The Patient-Reported Outcomes Measurement Information System (PROMIS) is a standardized patient-reported outcomes measure in pediatric and adult health with proven reliability and validity developed and supported by the National Institutes of Health (Irwin, Stucky, Langer, et al., 2010; Irwin, Stucky, Thissen, et al., 2010; Lai et al., 2013; Varni et al., 2014; Varni et al., 2010). The pediatric PROMIS self-report scales measure unidimensional health attributes (domains) of depressive symptoms, anxiety, anger, pain interference, peer relationships, fatigue, physical functioning including mobility and upper extremity function, and asthma impact (Varni et al., 2014). The pediatric PROMIS scales have been validated in children and adolescents with a variety of illnesses including cancer, kidney disease, asthma, obesity, arthritis, and SCD (Dampier, Barry, et al., 2016; DeWalt et al., 2015). PROMIS pediatric measures have been shown to be responsive to changes in health status associated with acute vaso-occlusive pain events requiring hospitalization in children with SCD, particularly patient-reported pain, fatigue, depressive symptoms and physical functioning (Dampier, Jaeger, et al., 2016). No study has determined if vitamin D supplementation can improve HRQL in children with type SS sickle cell disease (HbSS) using PROMIS.

The Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) tests for a wide range of neuromuscular motor skills including fine motor precision, balance, coordination and strength (Bruininks & Bruininks, 2005; Deitz, Kartin, & Kopp, 2007), and has been found to improve in children and young adults with HIV with 12-month high dose (7000 IU/day) vitamin D3 supplementation compared to placebo (Brown et al., 2015). Whether similar improvements in BOTMP scores occur in children with SCD or in healthy children after shorter term (3 months) high dose vitamin D supplementation has not yet been reported.

The purpose of this study was to assess the impact of high dose vitamin D supplementation over a 12-week period in 5-to 20-year old African American children with and without HbSS on: 1) HRQL using PROMIS; 2) physical performance including neuromuscular skills using BOTMP and 3) measures of muscle strength and function.

Methods

This was a secondary analysis of a randomized trial and the main methods and outcomes have previously been reported (Dougherty et al., 2015).

Participants

Five-to 20-year-old African American children with (n=21) and without (n=23) HbSS were recruited for a vitamin D supplementation study. Children with HbSS were recruited from the Comprehensive Sickle Cell Center at the Children’s Hospital of Philadelphia (CHOP) and healthy subjects from the CHOP network of primary care centers and the greater Philadelphia region. Exclusion criteria for both groups included: participation in another study impacting serum 25 hydroxyvitamin D (25(OH)D); pregnant or lactating females; other chronic conditions or use of medications affecting growth, dietary intake, or nutritional status; use of vitamin D to treat vitamin D deficiency; and baseline elevated serum calcium concentration. Subjects taking supplements containing vitamin D were not eligible. Those willing to discontinue supplementation with approval of their medical provider were eligible after a two-month washout period. Additional exclusion criterion for subjects with HbSS were chronic transfusion therapy and for healthy subjects were body mass index (BMI) >85th percentile for age and sex (Kuczmarski et al., 2000). Adipose tissue has long been identified as the major site of vitamin D storage (Blum et al., 2008), therefore children with a weight status category of overweight/obese were excluded.

This protocol was approved by the Institutional Review Board at CHOP. Written informed consent was obtained from subjects ages 18 to 20 years and parents / legal guardians of subjects <18 years. Verbal assent was obtained from subjects 6 to <18 years.

Study Design

Subjects within each group (HbSS or healthy) were randomized in the Spring (April-May), Summer (June-August) or Fall/Winter (September-January) to oral daily doses (4000 vs. 7000 IU) of cholecalciferol (vitamin D3) using a double-blind design and evaluated at baseline, 6 and 12 weeks. Safety was monitored weekly by study team and quarterly by an Independent Monitoring Committee.

Anthropometry, Pubertal Status, and Questionnaires

Anthropometric measurements were obtained in triplicate per standardized techniques (Lohman, Roche, & Martorell, 1988) and the mean used for analysis. BMI was calculated (kg/m2) from weight using a digital scale (Scaletronix, White Plains, NY) and standing height using a stadiometer (Holtain, Crymych, United Kingdom). Weight, height and BMI were compared to reference standards to generate age-and sex-specific Z scores (Kuczmarski et al., 2000). Total body fat and lean body mass were measured using whole body dual energy x-ray absorptiometry (DXA; Delphi A, Hologic, Inc., Bedford, MA) and compared with the Reference Project on Skeletal Development in Children data to generate race-and sex-specific DXA Z scores for lean body mass and fat mass relative to height (Foster, Platt, & Zemel, 2012). At baseline, pubertal status according to the criteria of Tanner (Tanner, 1962) was determined using a validated self-assessment questionnaire (Morris & Udry, 1980). Adherence (Dougherty et al., 2015) was assessed by questionnaire at 6-and 12-weeks and phone calls at weeks 1, 3, 5, 8, and 10 Subjects were interviewed at each visit documenting intensity and frequency of any adverse events (Dougherty et al., 2015).

Biochemistry and Hematology

Serum 25(OH)D was determined using liquid chromatography tandem mass spectrometry (Clinical Laboratory, CHOP) with intra and inter assay coefficients of variation below 7%. The justification for defining vitamin D status (25(OH)D concentration) as previously been reported (Dougherty et al., 2015): sufficient, ≥32 ng/ml; insufficient, <32 to 20 ng/ml; and deficient, <20 ng/ml. Hematologic status was assessed by complete blood count for all subjects and fetal hemoglobin was assessed in HbSS only according to standardized techniques. Serum high-sensitivity C-reactive protein (HS-CRP) was assessed in all subjects as an indicator of inflammatory status. Subjects with HbSS were categorized as receiving or not receiving hydroxyurea therapy during the study.

Health-Related Quality of Life

HRQL was assessed using the following PROMIS pediatric short forms: depressive symptoms, fatigue, pain, mobility, peer relationships and upper-extremity function. For PROMIS assessment of item response theory-based T-scores (population mean of 50 and SD of 10) in the depressive symptoms, fatigue, and pain domains, a higher T score indicates a worse outcome and, in the mobility, peer relationships, and upper-extremity function domains a lower T scores indicate a worse outcome.

Neuromuscular Motor Skills

The BOTMP (Bruininks & Bruininks, 2005) consists of 14 measures that represent eight neuromuscular motor skill domains. These include fine motor precision (line drawing, fold paper), fine motor integration (copy square, copy star), manual dexterity (penny transfer), bilateral coordination (jump in place, tap feet and fingers), balance (line walk, one leg balance), speed and agility (one leg hop), upper limb coordination (drop/catch ball, dribble ball), and strength (push-ups, sit-ups). Measurement details and scoring for each motor skill are described elsewhere (Bruininks & Bruininks, 2005). The total BOTMP score combines results from all skills for an overall score of motor proficiency, and higher scores indicate greater neuromuscular motor skill proficiency. Test-retest reliability (r=0.8) and criterion-related validity when compared to other measures of motor performance (r=0.74) are excellent for the BOTMP (Deitz et al., 2007).

Muscle Strength and Function

All subjects completed a 5-minute warm-up period of treadmill walking at a comfortable self-selected speed at 0% grade. Next, maximal handgrip strength of the right and left hand was measured in kilograms (kg) with a handgrip dynamometer (Takei Scientific Instruments Co., Ltd., Tokyo, Japan). Hand dominance was determined by asking which hand was used to hold a pencil. The participants stood upright with the shoulder adducted holding the dynamometer, not touching the trunk. The handle was adjusted to the hand size of the child and no extraneous body movement was allowed during testing. For each hand, three maximal effort trials lasting 4-seconds to 5-seconds interspersed with 60-second rests were carried out (verbal encouragement provided).

Peak power in watts (W) was calculated from the force-time curve and velocity of the center of mass during a maximal vertical squat jump using a Kistler Quattro Jump Portable Force Plate System (Model 9290AD, Kistler Instrument Corporation, Amherst, NY). Participants completed three warm-ups followed by three maximal vertical jumps from an initial static squat position with knees at 90 degrees flexion and arms akimbo. The highest value was used for analysis (McKay et al., 2005; Toumi et al., 2007).

Muscle torque was assessed using the Biodex Multi-Joint System 3 Pro (Biodex Medical Systems, Inc, Shirley, NY). High intrarater (0.97 to 0.99) and interrater (0.93 to 0.96) intraclass correlation coefficients have been reported for this method testing various body joints (Leggin, Neuman, Iannotti, Williams, & Thompson, 1996). Prior to testing each subject was familiarized with the test procedures. Plantar-and dorsiflexion isometric maximal voluntary contraction (MVC) torques of the left ankle were measured in triplicate at each of four angles (−10, 0, 10, and 20 degrees) and the highest value in Newton meters (Nm) recorded for dorsiflexion and plantarflexion at each angle. Isokinetic knee flexion and extension peak torque (Nm) was measured in triplicate at 1.05 rad/s (60 degrees/second) and the highest value recorded for extension and flexion of the left knee.

Statistical Analyses

All variables were tested for normality, and nonparametric tests were used as appropriate. At baseline, differences between groups (HbSS vs. healthy), at different doses (HbSS vs. healthy at 4,000 IU; HbSS vs. healthy at 7,000 IU) and within group at different doses (4,000 vs. 7,000 IU in HbSS; 4,000 vs. 7,000 IU in healthy) were determined by using a Student’s t test or Wilcoxon’s rank-sum test for continuous variables and Fisher’s exact or chi-square test for categorical variables. Longitudinal-mixed-effects (LME) analyses (Laird & Ware, 1982) were used to examine change over time and whether patterns of change were different between HbSS vs. healthy groups, with vitamin D dose group combined. Preliminary analysis did not find any statistically significant difference by dose in physical performance or health-related quality of life outcomes, thus dose groups were combined. These analyses were made using the intention-to-treat model where all subjects are included regardless of adherence to the study protocol. Similar to multiple linear regression analysis, LME analysis allows for multiple observations per subject. LME assumes that observations measured from the same subject are dependent and, therefore, the regression coefficients vary across subjects and are considered to be random. Also, it allows for unequal intervals between visits, uses data from all subjects, even when some study visits were missed, and accommodates both fixed and random effects. Parameter estimates, as in regression analysis, indicate the contribution of the independent variable to the model. For these LME analyses which controlled for baseline value, subject was treated as a random effect and measurement and time as fixed effects. All statistical analyses were performed by using STATA 14 (Stata Corp, College Station, TX). The results were considered significant at P<0.05 (unless otherwise indicated), and data are presented as means ± SDs (normal distribution).

Results

Twenty-one African American children with HbSS and 23 healthy African American controls of similar age and sex (Table 1) completed the study, receiving either 4000 or 7000 IU/day vitamin D3 for 12 weeks. Serum 25(OH)D at baseline was similar in HbSS (19.2 ± 7.2 ng/mL) and healthy children (22.3 ± 9.3 ng/mL). Children with HbSS had significantly poorer growth status for height, weight and BMI than the healthy children at baseline.

TABLE 1.

Subject Characteristics at Baseline and Vitamin D Concentrations and Baseline and 12 Weeks

HbSS 4,000 IU/day HbSS 7,000 IU/day Healthy All Healthy 4,000 IU/day Healthy 7,000 IU/day
HbSSa
ALL
N 21 12 9 23 11 12
Age (yr) 11 ± 4b 11 ± 4 10 ± 5 10 ± 4 9.7 ± 4.3 10.9 ± 3.5
Sex (% female) 57 58 56 43 27 58
Tanner (% 1 or 2) 67 67 67 57 64 50
On hydroxyurea (%) 43 33 56 --- --- ---
Height, (cm) 137.6 ± 20.5 139.2 ± 21.6 135.4 ± 20.0 141.5 ± 20.5 137.5 ± 23.5 145.1 ± 17.5
Height Z score −0.5 ± 1.2 −0.7 ± 1.3 −0.2 ± 0.9 0.4 ± 1.0* 0.3 ± 0.9 0.5 ± 1.0
Weight, (kg) 33.7 ± 15.4 32.6 ± 13.6 35.2 ± 18.3 43.9 ± 20.8 44.1 ± 27.4 43.7 ± 13.5
Weight Z score −0.7 ± 1.2 −1.1 ± 1.1 −0.0 ± 1.1 0.8 ± 1.1* 0.9 ± 1.0 0.7 ± 1.3
BMI 16.9 ± 3.6 16.0 ± 2.2 18.0 ± 4.8 20.7 ± 5.7* 21.0 ± 6.8 20.4 ± 4.7
BMI Z score −0.6 ± 1.1 −1.0 ± 0.9 −0.0 ± 1.1 0.7 ± 1.1* 0.8 ± 1.1 0.6 ± 1.2
LBM – DXA (kg) 25.0 ± 9.8 24.5 ± 9.5 25.5 ± 10.8 31.1 ± 13.9 30.9 ± 18.2 31.1 ± 9.2
FM – DXA (kg) 8.8 ± 6.1 8.0 ± 4.2 9.8 ± 8.2 13.0 ± 8.8 13.3 ± 10.9 12.8 ± 6.9
LBM-for-height Z score −1.9 ± 1.0 −2.4 ± 0.8 −1.3 ± 1.0 −0.9 ± 1.4* −0.9 ± 1.5 −0.9 ± 1.3
FM-for-height Z score 0.2 ± 0.6 0.0 ± 0.2 0.4 ± 0.6 0.8 ± 0.8* 1.0 ± 0.5 0.6 ± 1.0
% FM 24.6 ± 5.1 24.0 ± 3.0 25.4 ± 7.2 28.0 ± 8.7 27.3 ± 8.6 28.5 ± 9.1
Total 25(OH)D (ng/mL) 19.2 ± 7.2 18.0 ± 7.0 20.8 ± 7.5 22.3 ± 9.3 22.8 ± 8.4 21.9 ± 10.4
Total 25(OH)D at 12 weeks (ng/mL) 44.9 ± 26.6** 38.1 ± 21.0** 53.1 ± 31.3** 42.2 ± 17.8** 43.7 ± 18.4** 40.5 ± 18.1**
Force plate Peak power (watts/kg) 30.8 ± 3.7 29.6 ± 4.3 32.6 ± 1.8 33.8 ± 6.8 33.5 ± 5.8 34.2 ± 7.9
Peak power (watts) 1054 ± 478 953 ± 401 1207 ± 568 1488 ± 811* 1513 ± 1098 1465 ± 467
Jump height 25.3 ± 5.2 23.6 ± 5.7 27.7 ± 3.3 28.0 ± 8.5 27.1 ± 8.2 28.8 ± 9.0
Biodex ankle: plantar flexion isometric MVC torques (Nm)
  −10° 44.7 ± 22.2 43.7 ± 19.1 46.o ± 26.9 53.6 ± 36.9 52.2 ± 46.4 54.8 ± 25.0
Biodex ankle: dorsiflexion isometric MVC torques (Nm)
  −10° 9.8 ± 5.7 9.6 ± 5.9 10.2 ± 5.7 12.5 ± 6.9 13.1 ± 8.7 11.9 ± 4.7
  0° 12.3 ± 7.3 11.6 ± 7.4 13.1 ± 7.4 15.7 ± 10.7 15.4 ± 12.0 15.9 ± 9.9
  10° 13.3 ± 8.3 12.9 ± 7.5 13.9 ± 9.8 16.9 ± 12.1 17.4 ± 15.7 16.5 ± 8.1
  20° 14.9 ± 9.3 13.9 ± 7.9 16.2 ± 11.3 18.1 ± 13.3 19.2 ± 18.0 17.1 ± 7.6
Biodex knee: extension peak torque (Nm) 60°/sec 49.6 ± 27.6 48.8 ± 23.3 51.7 ±34.0 65.8 ± 44.1 64.3 ± 57.9 67.1 ± 29.0
Biodex knee: flexion peak torque (Nm) 60°/sec 22.4 ± 13.3 21.7 ± 9.7 23.3 ± 17.7 25.5 ± 14.7 22.5 ± 16.7 28.2 ± 12.7
Dominate hand max (kg) 15.6 ± 8.6 14.8 ± 8.5 16.7 ± 8.5 22.7 ± 9.0 21.4 ± 9.6* 23.9 ± 8.0
Right hand max (kg) 15.6 ± 8.6 14.8 ± 8.5 16.7 ± 9.0 20.8 ± 10.0 19.3 ± 11.5 22.1 ± 8.8
Left hand max (kg) 15.2 ± 7.6 14.8 ± 6.4 15.8 ± 9.4 19.8 ± 10.4 19.6 ± 12.3 20.1 ± 8.9
  Total score 61.5 ± 14.0 64.3 ± 9.9 57.8 ± 18.1 62.3 ± 15.2 57.9 ± 16.0 66.3 ± 13.9
  Transferring pennies 12.3 ± 3.3 13.2 ± 2.1 11.2 ± 4.3 12.4 ± 4.6 10.9 ± 4.9 13.6 ± 4.1
  One-legged stationary hop 36.3 ± 7.9 36.8 ± 8.2 35.8 ± 8.0 31.3 ± 10.8 33.5 ± 10.2 29.3 ± 11.3
Dropping and catching a ball -both hands 4.2 ± 1.7 4.7 ± 1.2 3.6 ± 2.1 4.4 ± 1.5 4.5 ± 1.5 4.3 ± 1.5
Dribbling a ball – alternating hands 5.1 ± 4.3 6.0 ± 4.2 3.9 ± 4.2 6.3 ± 3.7 5.1 ± 3.8 7.5 ± 3.4
  Pushups 11.9 ± 8.5 14.1 ± 8.6 9.0 ± 8.0 16.0 ± 8.7 15.2 ± 8.5 16.7 ± 9.1
  Situps 11.9 ± 9.6 11.3 ± 8.4 12.8 ± 11.5 13.5 ± 7.1 11.2 ± 6.2 15.7 ± 7.5
Fetal Hemoglobin (%) 12.4 ± 5.8 9.7 ± 5.1 15.1 ± 5.4 --- --- ---
HS-CRP (mg/L) 3.0 ± 2.6 1.9 ± 1.9 4.0 ± 2.7 1.1 ± 1.5* 0.7 ± 0.7 1.5 ± 1.9
Hemoglobin (g/dL) 8.4 ± 1.0 8.1 ± 1.2 8.7 ± 0.8 13.0 ± 1.1* 13.1 ± 1.2 13.0 ± 1.1
Hematocrit (%) 25.9 ± 3.1 24.9 ± 3.3 27.0 ± 2.6 39.8 ± 3.1* 40.5 ± 3.7 39.3 ± 2.6
Platelets (x103μL) 522 ± 158 599 ± 174 436 ± 80 303 ± 6 4* 295.1 ± 60.6 310.4 ± 67.8
a

HbSS, type SS sickle cell disease; BMI, body mass index; LBM, lean body mass; FM, fat mass; MVC, maximal voluntary contraction; BOT, Bruininks-Oseretsky Test of Motor Proficiency; HS-CRP, high-sensitivity C-reactive protein; 25(OH)D, 25-hydroxyvitamin D.

b

Mean ± SD (all such values).

*

P<0.05, HbSS vs. Healthy.

P<0.05, 4,000 vs. 7,000 IU/day in HbSS.

**

P<0.05, 12 weeks vs. baseline.

High dose vitamin D supplementation was efficacious in improving vitamin status in both groups. After 12 weeks of supplementation, the mean increase in 25(OH)D was 25.6 ± 22.3 ng/ mL in subjects with HbSS and 20.5 ± 17.5ng/mL in healthy subjects (both P<0.05) In subjects with HbSS, fetal hemoglobin significantly increased (12.4 ± 5.8 vs. 14.0 ± 6.2%), and HS-CRP decreased (3.0 ± 2.6 vs. 2.0 ± 1.7 mg/L) with vitamin D3. Ten children (48%) were receiving hydroxyurea therapy at the time of the study.

At baseline, based on PROMIS domain T scores, healthy children reported significantly less pain, fatigue and had greater mobility than children with HbSS (P<0.05). After 12-week vitamin D supplementation (Table 2), children with HbSS showed significant (P<0.05) declines in pain, fatigue and depressive symptoms T scores and an increased upper extremity function T score, with no difference in mobility or peer relationships. Healthy subjects also had a significant (P<0.05) decline in fatigue and improvement in upper-extremity function T scores, with no change in pain, depressive symptoms, mobility or peer relationships T scores. Children with HbSS showed steady and incremental improvement in T scores from baseline to 6 weeks and 12 weeks, while the patterns of change varied in healthy children over the domains.

TABLE 2.

Patient-Reported Outcomes Measurement Information System (PROMIS)

n Baseline n 6 Weeks n 12 Weeks
Pediatric Physical
Function – Upper
Extremity T Score
  Healthy 23 50.6 ± 8.8 20 52.5 ± 6.7 19 53.2 ± 6.4*
  HbSSa 21 45.9 ± 10.9 21 47.8 ± 9.5 20 51.2 ± 8.7**
Pediatric Physical
Function – Mobility
T Score
  Healthy 23 57.8 ± 3.3 20 58.1 ± 2.9 19 57.5 ± 3.7
  HbSS 21 53.1 ± 6.2* 21 55.2 ± 5.1** 20 55.7 ± 5.4
Pediatric Peer
Relationships T Score
  Healthy 23 56.0 ± 7.3 20 57.2 ± 7.8 19 56.1 ± 9.2
  HbSS 21 56.9 ± 7.1 21 58.2 ± 8.5 20 57.8 ± 11.0
Pediatric Pain Impact
T Score
  Healthy 23 48.6 ± 8.7 20 49.9 ± 10.1 19 48.9 ± 7.3
  HbSS 21 54.4 ± 13.3* 21 52.7 ± 13.2** 20 48.4 ± 14.8‡‡
Pediatric Fatigue
T Score
  Healthy 23 40.3 ± 10.3 20 43.3 ± 12.4 19 36.3 ± 10.0
  HbSS 21 51.7 ± 11.4* 21 48.6 ± 10.2 20 46.4 ± 14.0‡‡***
Pediatric Depressive
Symptoms T Score
  Healthy 23 41.5 ± 8.2 20 37.4 ± 7.6 19 39.9 ± 9.4
  HbSS 21 43.1 ± 8.1 21 39.1 ± 5.8†† 20 39.1 ± 7.3‡‡
a

HbSS, type SS sickle cell disease.

*

P<0.05, HbSS vs. Healthy at baseline.

**

P<0.05, HbSS vs. Healthy at 6 Weeks.

***

P<0.05, HbSS vs. Healthy at 12 Weeks.

P<0.05, 6 Weeks vs. Baseline in Healthy.

††

P<0.05, 6 Weeks vs. Baseline in HbSS.

P<0.05, 12 Weeks vs. Baseline in Healthy.

‡‡

P<0.05, 12 Weeks vs. Baseline in HbSS.

Healthy children did not differ from children with HbSS at baseline, 6-, or 12-weeks in neuromuscular motor skills based upon BOTMP (Table 3). After 12-week vitamin D supplementation, children with HbSS improved significantly (P<0.05) in the total BOTMP score, and particularly for strength (push-ups and sit-ups) and upper limb coordination (drop/catch and dribble ball). Healthy children also showed significant (P<0.05) improvement in the total BOTMP score with supplementation and particularly for manual dexterity (penny transfer), fine motor integration (copy star) and speed and agility (one leg hop).

TABLE 3.

Bruininks-Oseretsky Test of Motor Proficiency (BOT) Outcomes

n Baseline n 6 Weeks n 12 Weeks
Total score
  Healthy 23 62.3 ± 15.2 20 64.8 ± 14.4 19 67.2 ± 10.3
  HbSSa 21 61.5 ± 14.0 21 64.5 ± 11.5 20 66.4 ± 10.3‡‡
Subscales
Fine motor precision
  Drawing lines through
  paths – crooked
   Healthy 23 2.6 ± 4.9 20 3.6 ± 6.7 19 1.9 ± 3.7
   HbSS 21 0.6 ± 1.0 21 0.9 ± 1.5 20 1.1 ± 2.3
  Folding paper
   Healthy 23 8.9 ± 3.5 20 8.8 ± 4.4 19 9.6 ± 3.3
   HbSS 21 8.4 ± 4.0 21 8.4 ± 3.8 20 8.7 ± 3.5
Fine motor integration
  Copying a square
   Healthy 23 4.5 ± 1.2 20 4.1 ± 1.6 19 4.9 ± 0.2
   HbSS 21 4.6 ± 1.2 21 4.6 ± 1.1 20 4.6 ± 0.8
  Copying a star
   Healthy 23 2.5 ± 2.2 20 3.1 ± 2.1 19 3.3 ± 1.8
   HbSS 21 2.9 ± 2.0 21 3.5 ± 1.6 20 3.6 ± 1.5
Manual dexterity
  Transferring pennies
   Healthy 23 12.3 ± 4.6 20 13.1 ± 4.4 19 13.2 ± 4.0
   HbSS 21 12.3 ± 3.3 21 12.7 ± 4.0 20 13.1 ± 4.6
Bilateral coordination
  Jumping in place – same sides synchronized
   Healthy 23 4.8 ± 1.0 20 5.0 ± 0.0 19 5.0 ± 0.0
   HbSS 21 4.8 ± 1.1 21 4.8 ± 0.9 20 4.8 ± 1.1
  Tapping feet and fingers – same side synchronized
   Healthy 23 9.4 ± 2.1 20 10.0 ± 0.0 19 10.0 ± 0.0
   HbSS 21 10.0 ± 0.0 21 10.0 ± 0.0 20 10.0 ± 0.0
Balance
  Walking forward on line
   Healthy 23 6.0 ± 0.2 20 6.0 ± 0.0 19 6.0 ± 0.0
   HbSS 21 5.8 ± 1.1 21 6.0 ± 0.0 20 6.0 ± 0.0
  Standing on one leg on a balance beam – eyes open
   Healthy 23 7.5 ± 3.1 20 8.0 ± 2.8 19 8.6 ± 2.7
   HbSS 21 8.6 ± 2.6 21 8.7 ± 2.1 20 8.8 ± 2.4
Speed and agility
  One-legged stationary hop
   Healthy 23 31.3 ± 10.8 20 32.1 ± 11.5 19 36.2 ± 6.2
   HbSS 21 36.3 ± 7.9 21 33.9 ± 7.2 20 37.6 ± 7.6
Upper limb coordination
 Dropping and catching a ball – both hands
   Healthy 23 4.4 ± 1.5 20 4.7 ± 1.2 19 4.7 ± 0.7
   HbSS 21 4.2 ± 1.7 21 4.2 ± 1.4 20 4.7 ± 0.7‡‡
  Dribbling a ball – alternating hands
   Healthy 23 6.3 ± 3.7 20 6.9 ± 3.2 19 7.3 ± 3.2
   HbSS 21 5.1 ± 4.3 21 5.5 ± 3.6 20 5.8 ± 3.9‡‡
Strength
  Pushups
   Healthy 23 16.0 ± 8.7 20 18.1 ± 7.2 19 15.2 ± 6.6
   HbSS 21 11.9 ± 8.5 21 16.0 ± 5.4 20 16.3 ± 5.4‡‡
  Situps
   Healthy 23 13.5 ± 7.1 20 18.2 ± 6.8 19 16.9 ± 6.1
   HbSS 21 11.9 ± 9.6 21 16.6 ± 6.7 20 17.8 ± 7.9‡‡
a

HbSS, type SS sickle cell disease.

P<0.05, 12 Weeks vs. Baseline in Healthy.

‡‡

P<0.05, 12 Weeks vs. Baseline in HbSS.

At baseline, children with HbSS had significantly lower dominant hand maximal handgrip strength, peak power, and plantar flexion isometric MVC torques at 10° and 20° angles (Table 4). After 12-week vitamin D supplementation (Table 4), significant improvements (P<0.05) in peak power and dorsiflexion isometric MVC torques at the 20° angle were observed in both groups. Additionally, in children with HbSS, significant improvements (P<0.05) in plantar flexion isometric MVC torques at the −10° angle and dorsiflexion isometric MVC torques at the −10° and 0° angles were observed.

TABLE 4.

Muscle Strength, Power and Torque Outcomes

n Baseline n 6 Weeks n 12 Weeks
Force plate
Peak power (watts)
  Healthy 23 1487.6 ± 811.1 19 1662.2 ± 848.6 19 1658.3 ± 888.9
  HbSSa 20 1054.3 ± 477.8* 20 1066.3 ± 577.9** 20 1071.1 ± 537.2‡‡,***
Jump height (cm)
  Healthy 23 28.0 ± 8.5 19 27.8 ± 7.6 19 27.7 ± 8.3
  HbSS 20 25.2 ± 5.2 20 25.1 ± 5.5 20 25.6 ± 5.8
Biodex Ankle
Plantar flexion isometric MVC torques (Nm)
−10°
  Healthy 21 53.6 ± 36.9 19 62.3 ± 44.2 18 64.6 ± 42.5
  HbSS 21 44.7 ± 22.2 21 50.7 ± 33.1 20 52.5 ± 31.6‡‡
  Healthy 22 50.0 ± 31.0 20 52.0 ± 31.8 19 53.7 ± 28.9
  HbSS 21 39.0 ± 20.0 21 43.3 ° 26.3 20 39.6 ± 21.6
10°
  Healthy 23 42.2 ± 24.7 20 43.4 ± 24.5 19 44.1 ± 23.2
  HbSS 21 27.3 ± 17.1* 34.1 ± 21.4 20 31.1 ± 17.0
20°
  Healthy 23 33.5 ± 19.5 20 32.7 ± 17.4 19 35.5 ± 19.0
  HbSS 21 21.2 ± 11.8* 21 23.6 ± 16.2 20 23.0 ± 13.5***
Dorsiflexion isometric MVC torques (Nm)
−10°
  Healthy 21 12.5 ± 6.9 9.8 ± 5.7 19 13.6 ± 8.9 18 13.5 ± 9.1
  HbSS 21 9.8 ± 5.7 21 9.8 ± 4.8 20 11.6 ± 6.7‡‡
 Healthy 22 15.7 ± 10.7 20 16.4 ± 11.1 19 17.0 ± 10.0
  HbSS 21 12.3 ± 7.3 21 12.6 ± 7.9 20 14.5 ± 9.0‡‡
10°
  Healthy 23 16.9 ± 12.1 20 19.8 ± 13.0 19 22.6 ± 17.5
  HbSS 21 13.3 ± 8.3 21 15.4 ± 9.0 20 15.9 ± 9.9
20°
  Healthy 23 18.1 ± 13.4 20 20.5 ± 12.4 19 21.6 ± 12.9
  HbSS 21 14.9 ± 9.3 21 15.5 ± 8.6 20 17.3 ± 10.3‡‡
Biodex Knee
Extension peak torque (Nm) 60°/sec
  Healthy 23 65.8 ± 44.1 20 69.0 ± 44.2 19 64.3 ± 42.8
  HbSS 21 49.6 ± 27.6 21 47.8 ± 27.6 20 41.8 ± 21.1***
Flexion peak torque (Nm)
60°/sec
  Healthy 23 25.5 ± 14.7 20 29.2 ± 19.2 19 29.8 ± 20.4
  HbSS 21 22.4 ± 13.3 21 23.2 ± 11.7 20 21.7 ± 11.5
Handgrip
Dominate hand max (kg)
  Healthy 23 22.7 ± 9.6 20 21.9 ± 9.9 19 24.1 ± 9.2
  HbSS 21 15.6 ± 8.6* 21 16.2 ± 7.9** 20 16.5 ± 7.8***
a

HbSS, type SS sickle cell disease; MVC, maximal voluntary contraction.

*

P<0.05, HbSS vs. Healthy at baseline.

**

P<0.05, HbSS vs. Healthy at 6 Weeks.

****

P<0.05, HbSS vs. Healthy at 12 Weeks.

P<0.05, 12 Weeks vs. Baseline in Healthy.

‡‡

P<0.05, 12 Weeks vs. Baseline in HbSS.

Discussion

Daily high-dose vitamin D supplementation for African American children with and without HbSS improved HRQL and physical performance. These improvements were accompanied by improvement in serum vitamin D status for both groups, and, in children with HbSS, improvement in clinical status (fetal hemoglobin) and inflammatory status. These findings highlight the beneficial pleiotropic effects of vitamin D supplementation for children’s physical and mental development, and also suggest possible disease specific improvements in SCD with supplementation.

Vitamin D deficiency is prevalent in people with SCD and is linked to acute and chronic pain and bone fracture in this population (Adegoke et al., 2017; Han et al., 2018; Osunkwo et al., 2011). Vitamin D status has also been associated with greater SCD disease severity (Gregoire-Pelchat et al., 2018; McCaskill et al., 2018). High dose vitamin D3 supplementation is safe and efficacious in SCD. We have previously demonstrated that 12-week high dose vitamin D3 supplementation (4000 or 7000IU/day) was safe and efficacious in improving serum 25(OH)D in both children with HbSS and healthy children (Dougherty et al., 2015). Vitamin D deficiency (25(OH)D of <20 ng/mL) was eliminated for both groups receiving the highest D3 dose. For children with HbSS, vitamin supplementation improved their clinical status with increased fetal hemoglobin, decreased inflammatory status and reduced platelet counts (Dougherty et al., 2015). A two-year supplementation (monthly oral 100,000IU or 12,000IU) study improved annual rates of respiratory illness in 3 to 20 year old children with SCD (reduction of >50%)(Lee et al., 2018). While other vitamin D supplementation trials in SCD have been conducted, many have not been of sufficient size or quality to inform clinical practice. Future large scale randomized, double-blind, placebo-controlled trials of vitamin D supplementation are needed.

Children with HbSS as well as those with other chronic illnesses, have poorer patient-reported HRQL than healthy children (Dale et al., 2011; Panepinto & Bonner, 2012; Panepinto et al., 2005; Wrotniak et al., 2014). Results from the present study are in agreement. In adults and children, the severity of SCD has been associated with worse PROMIS T scores in many domains compared to the general population (Dampier, Barry, et al., 2016; Dampier, Jaeger, et al., 2016; Keller, Yang, Treadwell, & Hassell, 2017; Reeve et al., 2018). In the present study, improvements ranging from 4 to 6 T score points in pain, fatigue, depression, and upper extremity function in HbSS after a relatively short period (12 weeks) of supplementation are considered major changes given that the minimally important difference in PROMIS T scores is considered to be a change of 3 points (Reeve et al., 2018; Thissen et al., 2016).

Pain and fatigue are particularly debilitating symptoms for children with HbSS, and have a particular impact on patient reported outcomes and quality of life (Ameringer, Elswick, & Smith, 2014; Anderson, Allen, Thornburg, & Bonner, 2015; Bakshi, Lukombo, Belfer, & Krishnamurti, 2018; Bakshi, Ross, & Krishnamurti, 2018; Dampier, Jaeger, et al., 2016; Dewalt et al., 2013). In a meta-analysis, vitamin D was shown to decrease pain scores and improve pain in people with chronic widespread pain (Yong, Sanguankeo, & Upala, 2017). The results of this study suggest that high dose vitamin D holds promise to improve pain and fatigue symptoms and overall HRQL in children with SCD, however further study is needed to show sustained or enhanced improvement with longer term supplementation.

High dose vitamin D3 may play a role in improving physical performance in children with and without chronic illness. Vitamin D receptors are present in the nucleus and on the membrane of human muscle cells. Genomic effects are through binding of 1,25-dihydroxyvitamin D to the nuclear vitamin D receptor and include gene transcription of mRNA and protein synthesis influencing muscle calcium transport and phospholipid metabolism. Nongenomic effects act via second messenger pathways to regulate intracellular calcium transport and stimulate muscle cell proliferation and growth (Bartoszewska, Kamboj, & Patel, 2010). In vitamin D deficient adults, the atrophy of type II fast twitch muscle fibers, which are essential for rapid movement in emergency situations and routine activities of daily living, is reversible with vitamin D supplementation (Ceglia, 2009; Hamilton, 2010). Moreover, several randomized controlled trials in older healthy adults demonstrated an improvement in neuromuscular functioning, including balance, reaction time and muscle strength and performance with vitamin D supplementation (Cannell, Hollis, Sorenson, Taft, & Anderson, 2009). In the present study, significant improvement in neuromuscular motor skills (total BOTMP) with vitamin D supplementation was evident for both children with HbSS and healthy children, although the improvements tended to be in different domains for the two groups. This improvement is consistent with the significant reduction in fatigue all children reported in PROMIS. Also, for children with HbSS, the patient-reported improvement in upper extremity function (PROMIS) is consistent with improvement seen in upper limb coordination in the BOTMP.

Children with HbSS have been shown to have muscle strength, power and torque deficits compared to healthy children of similar age, race and sex (Dougherty et al., 2018; Dougherty et al., 2011). In this study we report improvements in muscle power and torque with vitamin D3 supplementation for both children with HbSS and healthy children. These improvements in tests of muscle strength and function are consistent with reported reductions in both pain and fatigue, and improvements in physical function in children with HbSS and in the reported reduction in fatigue and improvement in physical function in healthy children based on PROMIS. Future studies investigating the potential of vitamin D to improve physical functioning and HRQL in SCD are warranted.

In conclusion, daily high-dose vitamin D supplementation improved HRQL, muscle strength and physical performance in children with and without HbSS. The significance of these findings relates to overall health; vitamin D supplementation may prove to be an effective and feasible treatment for symptoms and prevention of complications for people of all ages living with HbSS in the US and around the world. In this study cohort, only the 7000 IU/d dose effectively treated deficiency (25(OH)D of <20 ng/mL) in both HbSS and healthy participants. This highlights the need for full-scale randomized double-blind placebo-controlled trials to test the impact of higher D3 doses on HRQL and physical performance in children and young adults with HbSS and their healthy counterparts.

Acknowledgments

We are grateful to the subjects and their families for study participation and to our many colleagues. We thank the Center for Human Phenomic Science, CHOP Nutrition Center and CHOP Comprehensive Sickle Cell Center.

Funding

This study was supported by the National Center for Research Resources, Grant UL1RR024134, which is now at the National Center for Advancing Translational Sciences, Grant UL1TR000003, K12 (KL2RR024132), K23 (K23HL114637), and the Metabolism, Nutrition and Development Research Affinity Group Pilot and Feasibility Grant, Gastroenterology Research and Education Fund Grant, and Nutrition Center at The Children’s Hospital of Philadelphia.

Footnotes

Declaration of Conflicting Interests

The authors declare that there is no conflict of interest.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributor Information

Kelly A. Dougherty, School of Health Sciences, Stockton University, Galloway, NJ.

Joan I. Schall, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Chiara Bertolaso, Johns Hopkins University, Department of Pediatrics, Baltimore, MD.

Kim Smith-Whitley, Comprehensive Sickle Cell Center; Clinical Director, Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Virginia A. Stallings, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

References

  1. Adegoke SA, Oyelami OA, Adekile A, & Figueiredo MS (2017). Influence of serum 25-hydroxyvitamin D on the rate of pain episodes in Nigerian children with sickle cell anaemia. Paediatr Int Child Health, 37(3), 217–221. doi: 10.1080/20469047.2017.1295012 [DOI] [PubMed] [Google Scholar]
  2. Ameringer S, Elswick RK Jr., & Smith W. (2014). Fatigue in adolescents and young adults with sickle cell disease: biological and behavioral correlates and health-related quality of life. Journal of Pediatric Oncology Nursing, 31(1), 6–17. doi: 10.1177/1043454213514632 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson LM, Allen TM, Thornburg CD, & Bonner MJ (2015). Fatigue in Children With Sickle Cell Disease: Association With Neurocognitive and Social-Emotional Functioning and Quality of Life. Journal of Pediatric Hematology/Oncology, 37(8), 584–589. doi: 10.1097/mph.0000000000000431 [DOI] [PubMed] [Google Scholar]
  4. Bakshi N, Lukombo I, Belfer I, & Krishnamurti L. (2018). Pain catastrophizing is associated with poorer health-related quality of life in pediatric patients with sickle cell disease. Journal of Pain Research, 11, 947–953. doi: 10.2147/jpr.s151198 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bakshi N, Ross D, & Krishnamurti L. (2018). Presence of pain on three or more days of the week is associated with worse patient reported outcomes in adults with sickle cell disease. Journal of Pain Research, 11, 313–318. doi: 10.2147/jpr.s150065 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bartoszewska M, Kamboj M, & Patel DR (2010). Vitamin D, muscle function, and exercise performance. Pediatr. Clin. North Am, 57(3), 849–861. [DOI] [PubMed] [Google Scholar]
  7. Blum M, Dolnikowski G, Seyoum E, Harris SS, Booth SL, Peterson J, … Dawson-Hughes B. (2008). Vitamin D(3) in fat tissue. Endocrine, 33(1), 90–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown JC, Schall JI, Rutstein RM, Leonard MB, Zemel BS, & Stallings VA (2015). The impact of vitamin D3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial. Journal of Musculoskeletal & Neuronal Interactions, 15(2), 145–153. [PMC free article] [PubMed] [Google Scholar]
  9. Bruininks RH, & Bruininks BD (2005). Bruininks-Oseretsky Test of Motor Proficiency (2 ed.). Minneapolis: Pearson Assessment. [Google Scholar]
  10. Cannell JJ, Hollis BW, Sorenson MB, Taft TN, & Anderson JJ (2009). Athletic performance and vitamin D. Med. Sci. Sports Exerc, 41(5), 1102–1110. [DOI] [PubMed] [Google Scholar]
  11. Ceglia L. (2009). Vitamin D and its role in skeletal muscle. Curr. Opin. Clin. Nutr. Metab Care, 12(6), 628–633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dale JC, Cochran CJ, Roy L, Jernigan E, & Buchanan GR (2011). Health-related quality of life in children and adolescents with sickle cell disease. Journal of Pediatric Health Care, 25(4), 208–215. doi: 10.1016/j.pedhc.2009.12.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dampier C, Barry V, Gross HE, Lui Y, Thornburg CD, DeWalt DA, & Reeve BB (2016). Initial Evaluation of the Pediatric PROMIS(R) Health Domains in Children and Adolescents With Sickle Cell Disease. Pediatric Blood & Cancer, 63(6), 1031–1037. doi: 10.1002/pbc.25944 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dampier C, Jaeger B, Gross HE, Barry V, Edwards L, Lui Y, … Reeve BB (2016). Responsiveness of PROMIS(R) Pediatric Measures to Hospitalizations for Sickle Pain and Subsequent Recovery. Pediatric Blood & Cancer, 63(6), 1038–1045. doi: 10.1002/pbc.25931 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Deitz JC, Kartin D, & Kopp K. (2007). Review of the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2). Phys. Occup. Ther. Pediatr, 27(4), 87–102. [PubMed] [Google Scholar]
  16. DeWalt DA, Gross HE, Gipson DS, Selewski DT, DeWitt EM, Dampier CD, … Varni JW (2015). PROMIS((R)) pediatric self-report scales distinguish subgroups of children within and across six common pediatric chronic health conditions. Quality of Life Research, 24(9), 2195–2208. doi: 10.1007/s11136-015-0953-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dewalt DA, Thissen D, Stucky BD, Langer MM, Morgan Dewitt E, Irwin DE, … Varni JW (2013). PROMIS Pediatric Peer Relationships Scale: development of a peer relationships item bank as part of social health measurement. Health Psychology, 32(10), 1093–1103. doi: 10.1037/a0032670 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dougherty KA, Bertolaso C, Schall JI, Smith-Whitley K, & Stallings VA (2015). Safety and Efficacy of High-dose Daily Vitamin D3 Supplementation in Children and Young Adults With Sickle Cell Disease. Journal of Pediatric Hematology/Oncology, 37(5), e308–315. doi: 10.1097/mph.0000000000000355 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dougherty KA, Bertolaso C, Schall JI, Smith-Whitley K, & Stallings VA (2018). Muscle Strength, Power, and Torque Deficits in Children With Type SS Sickle Cell Disease. Journal of Pediatric Hematology/Oncology, 40(5), 348–354. doi: 10.1097/mph.0000000000001143 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dougherty KA, Schall JI, Rovner AJ, Stallings VA, & Zemel BS (2011). Attenuated maximal muscle strength and peak power in children with sickle cell disease. Journal of Pediatric Hematology/Oncology, 33(2), 93–97. doi: 10.1097/MPH.0b013e318200ef49 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Foster BJ, Platt RW, & Zemel BS (2012). Development and validation of a predictive equation for lean body mass in children and adolescents. Annals of Human Biology, 39(3), 171–182. doi: 10.3109/03014460.2012.681800 [DOI] [PubMed] [Google Scholar]
  22. Gregoire-Pelchat P, Alos N, Ribault V, Pastore Y, Robitaille N, & Mailhot G. (2018). Vitamin D Intake and Status of Children With Sickle Cell Disease in Montreal, Canada. Journal of Pediatric Hematology/Oncology, 40(8), e531–e536. doi: 10.1097/mph.0000000000001306 [DOI] [PubMed] [Google Scholar]
  23. Hamilton B. (2010). Vitamin D and human skeletal muscle. Scandinavian Journal of Medicine and Science in Sports, 20(2), 182–190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Han J, Zhang X, Saraf SL, Gowhari M, Molokie RE, Hassan J, … Gordeuk VR (2018). Risk factors for vitamin D deficiency in sickle cell disease. British Journal of Haematology, 181(6), 828–835. doi: 10.1111/bjh.15270 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Irwin DE, Stucky B, Langer MM, Thissen D, Dewitt EM, Lai JS, … DeWalt, D. A. (2010). An item response analysis of the pediatric PROMIS anxiety and depressive symptoms scales. Quality of Life Research, 19(4), 595–607. doi: 10.1007/s11136-010-9619-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Irwin DE, Stucky BD, Thissen D, Dewitt EM, Lai JS, Yeatts K, … DeWalt DA (2010). Sampling plan and patient characteristics of the PROMIS pediatrics large-scale survey. Quality of Life Research, 19(4), 585–594. doi: 10.1007/s11136-010-9618-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Keller S, Yang M, Treadwell MJ, & Hassell KL (2017). Sensitivity of alternative measures of functioning and wellbeing for adults with sickle cell disease: comparison of PROMIS(R) to ASCQ-Me. Health Qual Life Outcomes, 15(1), 117. doi: 10.1186/s12955-017-0661-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, … Johnson (2000). CDC Growth Charts: United States (Advance data from vital and health statistics; no. 314 ed, pp. 1–28). Hyattsville, MD: National Center for Health Statistics. (Reprinted from: Not in File). [Google Scholar]
  29. Lai JS, Stucky BD, Thissen D, Varni JW, DeWitt EM, Irwin DE, … DeWalt DA (2013). Development and psychometric properties of the PROMIS((R)) pediatric fatigue item banks. Quality of Life Research, 22(9), 2417–2427. doi: 10.1007/s11136-013-0357-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Laird NM, & Ware JH (1982). Random-effects models for longitudinal data. Biometrics, 38(4), 963–974. [PubMed] [Google Scholar]
  31. Lee MT, Kattan M, Fennoy I, Arpadi SM, Miller RL, Cremers S, … Brittenham GM (2018). Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. Blood Adv, 2(9), 969–978. doi: 10.1182/bloodadvances.2017013979 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Leggin BG, Neuman RM, Iannotti JP, Williams GR, & Thompson EC (1996). Intrarater and interrater reliability of three isometric dynamometers in assessing shoulder strength. J. Shoulder Elbow Surg, 5(1), 18–24. [DOI] [PubMed] [Google Scholar]
  33. Lohman TG, Roche AR, & Martorell R. (1988). Anthropometric standardization reference manual. Champaign: Human Kinetics. [Google Scholar]
  34. McCaskill ML, Ogunsakin O, Hottor T, Harville EW, & Kruse-Jarres R. (2018). Serum 25-Hydroxyvitamin D and Diet Mediates Vaso-Occlusive Related Hospitalizations in Sickle-Cell Disease Patients. Nutrients, 10(10). doi: 10.3390/nu10101384 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. McKay H, Tsang G, Heinonen A, MacKelvie K, Sanderson D, & Khan KM (2005). Ground reaction forces associated with an effective elementary school based jumping intervention. Br. J. Sports Med, 39(1), 10–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Morris NM, & Udry JR (1980). Validation of a self-administered instrument to assess stage of adolescent development. J. Youth Adolesc, 9, 271–280. [DOI] [PubMed] [Google Scholar]
  37. Osunkwo I, Hodgman EI, Cherry K, Dampier C, Eckman J, Ziegler TR, … Tangpricha V. (2011). Vitamin D deficiency and chronic pain in sickle cell disease. Br. J. Haematol, 153, 538–540. [DOI] [PubMed] [Google Scholar]
  38. Panepinto JA, & Bonner M. (2012). Health-related quality of life in sickle cell disease: past, present, and future. Pediatric Blood & Cancer, 59(2), 377–385. doi: 10.1002/pbc.24176 [DOI] [PubMed] [Google Scholar]
  39. Panepinto JA, O’Mahar KM, DeBaun MR, Loberiza FR, & Scott JP (2005). Health-related quality of life in children with sickle cell disease: child and parent perception. British Journal of Haematology, 130(3), 437–444. doi: 10.1111/j.1365-2141.2005.05622.x [DOI] [PubMed] [Google Scholar]
  40. Reeve BB, Edwards LJ, Jaeger BC, Hinds PS, Dampier C, Gipson DS, … DeWalt A. (2018). Assessing responsiveness over time of the PROMIS((R)) pediatric symptom and function measures in cancer, nephrotic syndrome, and sickle cell disease. Quality of Life Research, 27(1), 249–257. doi: 10.1007/s11136-017-1697-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Soe HH, Abas AB, Than NN, Ni H, Singh J, Said AR, & Osunkwo I. (2017). Vitamin D supplementation for sickle cell disease. Cochrane Database Syst Rev, 1, Cd010858. doi: 10.1002/14651858.CD010858.pub2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tanner JM (1962). The development of the reproductive system Growth at Adolescence (2 ed., pp. 28–39). Oxford: Blackwell Science. (Reprinted from: Not in File). [Google Scholar]
  43. Thissen D, Liu Y, Magnus B, Quinn H, Gipson DS, Dampier C, … DeWalt DA (2016). Estimating minimally important difference (MID) in PROMIS pediatric measures using the scale-judgment method. Quality of Life Research, 25(1), 13–23. doi: 10.1007/s11136-015-1058-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Toumi H, Poumarat G, Benjamin M, Best TM, F’Guyer S, & Fairclough J. (2007). New insights into the function of the vastus medialis with clinical implications. Med. Sci. Sports Exerc, 39(7), 1153–1159. [DOI] [PubMed] [Google Scholar]
  45. Varni JW, Magnus B, Stucky BD, Liu Y, Quinn H, Thissen D, … DeWalt DA (2014). Psychometric properties of the PROMIS (R) pediatric scales: precision, stability, and comparison of different scoring and administration options. Quality of Life Research, 23(4), 1233–1243. doi: 10.1007/s11136-013-0544-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Varni JW, Stucky BD, Thissen D, Dewitt EM, Irwin DE, Lai JS, … Dewalt DA (2010). PROMIS Pediatric Pain Interference Scale: an item response theory analysis of the pediatric pain item bank. Journal of Pain, 11(11), 1109–1119. doi: 10.1016/j.jpain.2010.02.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wrotniak BH, Schall JI, Brault ME, Balmer DF, & Stallings VA (2014). Health-related quality of life in children with sickle cell disease using the child health questionnaire. Journal of Pediatric Health Care, 28(1), 14–22. doi: 10.1016/j.pedhc.2012.09.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yong WC, Sanguankeo A, & Upala S. (2017). Effect of vitamin D supplementation in chronic widespread pain: a systematic review and meta-analysis. Clinical Rheumatology, 36(12), 2825–2833. doi: 10.1007/s10067-017-3754-y [DOI] [PubMed] [Google Scholar]

RESOURCES