Body Composition Abnormalities in Long-Term Survivors of Pediatric Hematopoietic Stem Cell...

Body Composition Abnormalities in Long-Term Survivors ofPediatric Hematopoietic Stem Cell Transplantation

Sogol Mostoufi-Moab, MD; MSCE1,2,*, Jill P. Ginsberg, MD1, Nancy Bunin, MD1, Babette S.Zemel, PhD3, Justine Shults, PhD3,5, Meena Thayu, MD; MSCE3, and Mary B. Leonard, MD;MSCE4,5

1The Children’s Hospital of Philadelphia, Department of Pediatrics, Division of Oncology2The Children’s Hospital of Philadelphia, Department of Pediatrics, Division of Endocrinology3The Children’s Hospital of Philadelphia, Department of Pediatrics, Division of Gastroenterology,Hepatology, and Nutrition4The Children’s Hospital of Philadelphia, Department of Pediatrics, Division of Nephrology5Department of Biostatistics and Epidemiology, The University of Pennsylvania School ofMedicine

AbstractObjective—To quantify lean mass (LM) and fat mass (FM) in survivors of childhood allogeneichematopoietic stem-cell transplantation (alloHSCT) compared with healthy reference participants,and identify risk factors for body composition abnormalities.

Study design—Whole body LM and FM were measured bydual energy x-ray absorptiometry in54 survivors (ages 5–25 yr) and 894 healthy reference participants in a cross-sectional study.Multivariate regression models were used to compare sex-and race- specific Z-scores for LM(LM-Ht-Z) and FM (FM-Ht-Z) relative to height in survivors and reference participants, and toidentify correlates of LM-Ht-Z and FM-Ht-Z in alloHSCT.

Results—Height-Z was significantly lower in alloHSCT (P<0.001) vs. reference participants;BMI-Z did not differ (P=0.13). Survivors had significantly lower mean LM-Ht-Z [−0.72 (95% CI:−1.02, −0.42);P<0.001] and greater FM-Ht-Z[1.10 (95% CI:0.84, 1.39;P<0.001], compared withreference participants. LM-Ht-Z deficits in alloHSCTwere larger [−1.26(95% CI:−1.53,−0.99;P<0.001] after adjustment for FM-Ht-Z. Endocrinopathies and alloHSCT characteristicswere not associated with LM-Ht-Z or FM-Ht-Z.

Conclusions—Survivors of childhood alloHSCT have significant LM deficits and FM excess.Future studies should identify the mechanism and consequences of these abnormalities.

KeywordsAllogeneic hematopoietic stem cell transplantation; growth failure; body composition; LM; fatmass

© 2011 Mosby, Inc. All rights reserved.*Corresponding author: SogolMostoufi-Moab, MD; MSCE, The Children’s Hospital of Philadelphia, 3535 Market Street,Philadelphia, PA19104, 267 426-9725 Business Phone, 215 590-0604, Fax, moab@email.chop.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review ofthe resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

NIH Public AccessAuthor ManuscriptJ Pediatr. Author manuscript; available in PMC 2013 January 1.

Published in final edited form as:J Pediatr. 2012 January ; 160(1): 122–128. doi:10.1016/j.jpeds.2011.06.041.

-PA Author Manuscript

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) is an established treatmentfor bone marrow failure syndromes and hematologic malignancies in children. Current fiveyear cure rates exceed 60%.1, 2 As survival has improved, focus has shifted to the long-termcomplications of alloHSCT. Survivors of alloHSCT have numerous risk factors forabnormal body composition such as nutritional deficiencies,3–7 glucocorticoid therapy,decreased physical activity,8 and endocrine abnormalities as a consequence of chemotherapyand radiation.9 Dysregulation of the immune system with concomitant elevated cytokinerelease and graft-versus-host-disease (GVHD) impose additional threats to bodycomposition.10, 11

A recent Childhood Cancer Survivor Study (CCCS) of self-reported body mass index (BMI,kg/m2) in over 7000 adult survivors identified subsets of patients at risk for obesity orunderweight.12 Underweight survivors were more likely to report adverse health outcomesand comorbidities. However, prior studies have illustrated the shortcomings of using BMI inpatients with inflammatory conditions: BMI does not distinguish between alterations in leanmass and fat mass, and excess fat mass may conceal lean mass deficits.13–18 Previousstudies using anthropometric measures, such as skinfold thickness, have identified lean massdeficits at the time of treatment for childhood malignancy,19–21 and fat mass excessfollowing therapy.22–26 Studies using dual energy x-ray absorptiometry (DXA) to measurebody composition have been limited to survivors of acute lymphoblastic leukemia.27–32

Furthermore, most studies describing body composition alterations in survivors of childhoodcancer included small number of patients and did not include a sufficiently robust controlpopulation necessary to characterize body composition relative to age, sex, race, maturationand body size. As a result, abnormalities in body composition in long term pediatricsurvivors of HSCT have not been well-characterized.

Analysis and interpretation of body composition data in children with chronic diseaserequire careful attention to sex-, maturation-, and race-related differences in lean and fatmass relative to body size. In contrast to BMI, DXA provides precise and accurate measuresof lean mass and fat mass in children and adults.13, 33, 34 Thus, the objectives of the presentstudy were to assess lean mass and fat mass in children and young adult survivors ofalloHSCT, compared with a large healthy reference group, and to identify risk factors foralterations in fat mass and lean mass in subjects after successful treatment with alloHSCT.

METHODSThe study population included 54 children and young adults, ages 5 to 25 years treated withan alloHSCT, currently followed at the Children’s Hospital of Philadelphia (CHOP).Inclusion criteria included at least a three year interval since diagnosis ofalloHSCT.Participants were excluded if they had a history of diseases known to affect bone healthincluding neuromuscular disease, inflammatory bowel disease, sickle cell anemia, activemalignancy, or renal dysfunction (estimated glomerular filtration rate < 60 ml/min/1.73m2).35

Participants with AlloHSCTwere compared with894 healthy reference participants, ages 5 to21 years. The reference participants were recruited from general pediatrics practices in thegreater Philadelphia area and through advertisementsto characterize bone and bodycomposition in healthy subjects, as previously described.16, 17, 36–43 The healthy referenceparticipants were excluded for known chronic illnesses or medications affecting growth anddevelopment.

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The study protocol was approved by the Institutional Review Board at CHOP. Informedconsent was obtained directly from study participants older than 18 years, and assent alongwith parental consent from participants less than 18 years of age.

All 54 participants underwent alloHSCT for leukemia or bone marrow failure syndrome.AlloHSCT characteristics, including date and type of primary diagnosis, date of HSCT,donor type (matched related or unrelated), conditioning regimen (including use and dose oftotal body irradiation), and history of acute or chronic GVHD were recorded. Myeloablativeconditioning regimens consisted of cyclophosphamide, thiotepa, and fractionated total bodyirradiation (range 1200–1320 cGy) or busulfan and cyclophosphamide. Non-myeloablativeregimens included busulfan and cytoxan +/− melphalan or fludarabine. All recipientsreceived cyclosporine A infusions, starting two days before transplantation, and the dosagewas adjusted to maintain plasma levels of 300 to 400 ng/mL. Prior to discharge, Cyclosporinwas transitioned to tacrolimus and discontinued by six months after alloHSCT in theabsence of GVHD.

For patients with GVHD, onset, duration and type of immunosuppressive regimen weredetermined. GVHD classification was based on a four-point scale (I indicating mild and IVsevere disease).44 Cumulative glucocorticoid exposure from the time of transplantation tothe date of the study visit was assessed through review of the medical record.Glucocorticoids were summarized as cumulative mg/kg and average mg/kg/day during theglucocorticoid treatment interval, as well as days since last glucocorticoid dose.

Participants and parents were interviewed at the study visit to review the medical historyincluding presence or absence of gonadal insufficiency, growth hormone deficiency (GHD),and thyroid disease. Endocrinopathy characteristics, such as GH, thyroid dysfunction, andhypogonadism were further delineated with detailed medical chart review.

Height was measured with a stadiometer (Holtain, Crymych, UK) and weight with a digitalscale (Scaletronix, White Plains, New York). For the alloHSCT group, pubertaldevelopment stage was determined according to the method of Tanner by a pediatricendocrinologist (SMM). For the healthy reference group, Tanner stage was determined usinga validated self-assessment questionnaire.45 Study participants and their parents were askedto categorize the participant’s race according to the National Institute of Health categories.

Whole body LM (kg) and FM (kg) were assessed by DXA using a Hologic Delphidensitometer (Bedford, MA) with a fan beam in the array mode (software version 12.4),excluding the head.17, 37 Measurements were performed using standard supine positioningtechniques. LM was calculated as fat-free mass minus bone mineral content. DXA is aprecise (CV 1%-4%)14 method that has been used extensively to describe age-, sex-, race-,and pubertal-maturation-related variability in body composition compartments.46, 47 Theinstrument was calibrated daily using an hydroxyapatite phantom and weekly with a whole-body phantom.

Statistical AnalysisAnalyses were conducted using STATA 11.0 (Stata, College Station, TX). A two-tailed P-value <0.05 was the criterion for statistical significance. Differences in means were assessedusing Studentt-test for normally distributed variables and Wilcoxon’s rank sum test for non-normally distributed variables, respectively. Group differences in categorical variables wereassessed by using the chi-square or Fisher exact test where appropriate. Correlationsbetween body composition Z-scores and continuous variables were assessed by Pearsonproduct moment correlations or Spearman rank correlations, as indicated.

Height and BMI were converted to age- and sex-specific standard deviation scores (Z-scores) in all subjects using National Center For Health Statistics 2000 Centers for DiseaseControl reference data.48 AlloHSCTwas associated with significantly lower height Z-scorescompared with controls, and body composition variables were highly correlated with heightin the reference participants (LM: R = 0.94, p < 0.001; FM: R = 0.57, p < 0.001). The bodycomposition results in the reference participants were used to generate sex- and race-specific curves for LM and FM relative to height using the LMS method,49 as previouslydescribed.16, 17, 36 This method addresses the greater variability in LM and FM in the tallersubjects and is the method used by the CDC to generate pediatric growth curves.49 The LMSresults were used to calculate LM for height (LM-Ht) and FM for height (FM-Ht) Z-scoresfor alloHSCT subjects and healthy reference participants. The LMS method does not allowsimultaneous adjustment for age and height; therefore, the LM-Ht and FM-Ht Z-scores wereadjusted for age and height using linear regression analysis to capture the differences in jointdistributions of age and height in recipients of alloHSCT and healthy referenceparticipants.36, 50 Delays in the onset and progression through puberty in children afteralloHSCT may contribute to abnormalities in body composition relative to age and height.Therefore, the LM-Ht and FM-Ht Z-scores were subsequently adjusted for Tanner stage ofpubertal maturation (with indicator variables for each Tanner stage). Lastly, as there was apositive association between LM-Ht and FM-Ht Z-scores in the subjects withalloHSCT(r=0.51, P< 0.001) and healthy reference participants (r=0.49, P< 0.001), the LM-Ht Z-score models were also adjusted for FM-Ht Z-scores to account for the positiveassociation between FM-Ht and LM-Ht Z-scores.37, 51, 52 Given the significant correlationbetween LM-Ht and FM-Ht Z-scores, the degree of variance inflation (vif) command inStata 11.0 was used to confirm model stability after addition of FM-Ht Z-score to the LM-HtZ-score regression models. Multiplicative interaction terms were used to determine if theassociation between alloHSCT and body composition Z-scores varied as a function ofsubject sex, race or Tanner stage. Interaction terms with sex were not significant. However,results are presented stratified on sex given sex-specific differences in the effects ofmaturation on body composition.

Additional multivariable linear regression models limited to subjects with alloHSCTwereused to identify potential determinants of LM-Ht and FM-Ht Z-scores, adjusted for age andheight, such as disease characteristics, conditioning regimen with TBI, presence or absenceof GVHD, glucocorticoid exposure, and endocrinopathies after alloHSCT.

Lastly, because participants with alloHSCT included ages up to 25 years and the healthyreference participants were less than 22 years of age, the analysis with alloHSCT andhealthy reference participants were repeated, limited to participants less than 22 years ofage. Given the substantial heterogeneity of the participants with alloHSCT, we alsoexamined the results within the two largest alloHSCT subgroups: acute myelogenousleukemia (AML, n = 23) and acute lymphoblastic leukemia (ALL, n = 12). The results inthese 35 participants were consistent with our findings in the entire sample.

RESULTSA total of 54 recipients of alloHSCT and 894 healthy reference subjects were enrolled.Subject characteristics are summarized in Table I. Pubertal maturation was delayed inrecipients of alloHSCT compared with reference participants: within Tanner stages 2, 3, and4, subjects with alloHSCTwere an average 2.1, 2.5, 2.8 years older (P< 0.01 for all),adjusted for sex and race. Subjects with AlloHSCT had significantly lower height-for-age Z-scores compared to healthy reference participants (P< 0.001); however, BMI-for-age Z-scores were not significantly different between groups (P= 0.13).

AlloHSCT disease characteristics are summarized in Table II. The median age was 7 yearsat time of alloHSCT and 15 years at time of the study. The median interval betweenalloHSCT and the study visit was 7 years (range 3 to 16 years). The most common diagnosisnecessitating alloHSCT was AML, with the majority receiving a matched-related donorsource. Three subjects (6%) required a second alloHSCT due to recurrence of disease. Thirtyeight (69%) received total body irradiation (TBI) as part of the alloHSCT conditioningregimen and 31 subjects (53%) did not experience GVHD. Among the 26 (48%) subjectstreated with glucocorticoids for GVHD, only one was still on glucocorticoids at the time ofthe study visit and the remainder had discontinued glucocorticoids at least 12 months prior.

Overall, 49 subjects with alloHSCT(90%) were diagnosed and treated for anendocrinopathy. Hypothyroidism was the most common endocrine diagnosis with 20subjects (37%) requiring treatment with thyroid replacement. Sixteen subjects (29%) werediagnosed with growth hormone deficiency (GHD), 14 (88%) received growth hormone(GH), and 8 (50%) were currently on GH. Among 10 girls with alloHSCT greater than 12years of age, seven were menarcheal, only 2 female subjects reported regular menses, and 5female subjects required hormone replacement for treatment-related ovarian failure. Sixmales (16%) required testosterone replacement for hypogonadism, all were 16 years or olderat time of replacement. Only 3 patients (5%) had a previous diagnosis of precocious pubertyrequiring treatment with Lupron during concomitant treatment with GH therapy. None hadhypocortisolism. All subjects with alloHSCT with diagnosis of endocrinopathy were onappropriate hormone replacement at the time of this study.

Adjusted FM-Ht Z-scores in subjects with alloHSCT, compared with healthy referenceparticipants are summarized in Table III. FM-Ht Z-scores were significantly greater insubjects with alloHSCT(P< 0.001), compared with healthy reference participants, adjustedfor age and height (Figure). FM-Ht Z-scores did not differ between male and female subjectswith alloHSCT (P= 0.69). Within healthy female reference participants, higher Tannerstages were associated with greater FM-Ht Z-scores (P< 0.001), adjusted for age and height.Adjustment for delayed maturation in female participants with alloHSCT resulted in agreater estimate of fat mass excess, compared with healthy reference participants (Table III).

Adjusted LM-Ht Z-scores in subjects with alloHSCT, compared with healthy referenceparticipants are summarized in Table III. LM-Ht Z-scores were significantly lower in maleand female subjects with alloHSCT (P< 0.001), compared with healthy referenceparticipants, adjusted for age and height (Figure). LM-Ht Z-scores did not differ betweenmale and female subjects with alloHSCT (P= 0.41). Within male and female healthyreference participants, greaterTanner stage was associated with greater LM-Ht Z-score,adjusted for age and height. Adjustment for delayed maturation in alloHSCT resulted in amodest attenuation of the LM deficits in male and female recipients with alloHSCT,compared with healthy reference participants (Table III). Adjustment for the greater FM-HtZ-scores in the subjects with alloHSCT revealed an even greater LM deficit in the subjectswith alloHSCT, compared with healthy reference participants (Table III).

LM-Ht and FM-Ht Z-scores in subjects with alloHSCTwere not associated with age atdiagnosis, age at time of alloHSCT, type of conditioning regimen, exposure to total bodyirradiation, or history of GVHD. Cumulative glucocorticoid exposure from time of HSCT tostudy date (mg/kg), average (mg/kg/day) during treatment interval, and days since lastglucocorticoid dose were not significantly associated with LM-Ht or FM-Ht Z-scoreabnormalities in subjects with alloHSCT. In addition, neither LM-Ht nor FM-Ht Z-scoreswere associated with endocrinopathies after alloHSCT. Analysis of alloHSCT and healthyreference participants limited to participants less than 22 years of age remained unchanged(data not shown). Repeat analysis limited to ALL and AML subgroups combined yielded

similar results: FM-Ht [β: 0.99 (95% CI: 0.63, 1.34 P< 0.001] and LM-Ht Z-scores [β:−0.81 (95% CI: −1.17, −0.45 P< 0.001], compared with the reference participants, adjustedfor age and height.

DISCUSSIONPrevious studies in survivors of childhood ALL without alloHSCT reported elevated whole-body percent fat, particularly after treatment with cranial radiation.32, 53 Pituitarydysfunction after exposure to cranial radiation or TBI is an established long-termconsequence of childhood cancer therapy.54 Nysomet al reported lower BMI with higher fatmass in 25 children with ALL after alloHSCT who were conditioned with TBI comparedwith healthy controls and ALL children treated with chemotherapy alone.55 These authorssuggested that cranial radiation and subsequent growth hormone insufficiency was aplausible explanation for muscle loss and excess fat in children after alloHSCT particularlyafter TBI.55 They also noted that BMI was a poor measure of body fatness in these patients.However, this study was limited by the lack of data on absolute lean mass and itsrelationship to the high percent fat in survivors. Couto-Silva et al reported lower BMI inchildren 2 to 5 years after alloHSCT with TBI compared to patients without TBI exposure,56

suggesting that TBI might play a role in lower lean body mass after alloHSCT. AlthoughGHD after cranial radiation or TBI exposure is a plausible explanation for lower lean massand elevated body fat noted in survivors, our data did not support exposure to TBI orpresence of GHD as contributing factors to deficits in LM-Ht or excess FM-Ht Z-scores insubjects with alloHSCT (P= 0.6 and P= 0.3 respectively). Other studies have suggested prioruse of dexamethasone or exposure to anthracyclines as a reason for elevated percent bodyfat.53, 57, 58 However, in this study, prior history of steroid use with either prednisone ordexamethasone was not associated with FM-Ht or LM-Ht Z-scores.

Systemic glucocorticoids have adverse effects on muscle and fat mass, with increasedadiposity as a well-recognized complication.59 Previous studies in children after high-doseglucocorticoid use for other disorders showed marked obesity without lean massdeficits.37, 60 Similarly, studies in subjects after renal transplant demonstrated initialincreases in fat mass secondary to glucocorticoids with subsequent increase in lean massbased on normal association between fat and lean mass.61–64 Our data did not suggest acorrelation between steroid use and current muscle deficits, and our cohort, with theexception of one patient who was still on treatment for chronic GVHD, either never receivedglucocorticoids or had not been treated with glucocorticoids for at least 12 months.

In this study, age- and sex-specific BMI Z-scores in subjects with alloHSCTwere notsignificantly different when compared to a large, robust sample of healthy referenceparticipants. However, LM-Ht Z-scores were significantly lower in subjects with alloHSCT,further highlighting the failure of BMI to capture discrete disease effects on lean mass andfat mass. Kyle et al also reported similar body composition abnormalities despite normalBMI in a longitudinal cohort of adult survivors of alloHSCT.5 Subjects with alloHSCT inour study exhibited significant delayed pubertal maturation compared with healthy referenceparticipants. LM-Ht Z-score deficits were not explained by low testosterone as only 6 HSCTmales (16%) in our cohort required testosterone replacement for gonadal failure.

The greatest limitations of this study are the cross-sectional design, modest sample size, andheterogeneous patient population. These limitations may account for the lack of associationsbetween disease and treatment characteristics and LM-Ht and FM-Ht Z-scores. In addition,all participants with endocrinopathies were on appropriate treatment, likely contributing tothe lack of association between these diagnoses and abnormalities in body composition.Nonetheless, this is the largest study to date describing body composition in alloHSCT and

the first to include a robust reference population. In addition, the limitation of the cohort tolong-term survivors decreased the heterogeneity related to treatments at the time of theevaluation; for example, only one subject had been treated with glucocorticoids in the prior12 months. Furthermore, secondary analyses within the two largest diagnostic subgroupsconfirmed the pattern of altered body composition seen in the larger sample. Additionalstudy limitations include differences in the assessment of Tanner stage in the alloHSCT andreference participants, and the lack of data on dietary intake, physical activity, or laboratorymeasures of inflammation. Therefore, this study provides little information regarding themechanism for the abnormal body composition but establishes the foundation for a largermulti-center study with longitudinal measures in selected subgroups.

The observed alterations in body composition with increased FM-Ht Z-scores in conjunctionwith lower lean mass may contribute to treatment-related morbidity and mortality associatedwith premature atherosclerotic cardiovascular disease, metabolic syndrome and poor bonehealth. Future longitudinal studies are necessary to determine the clinical significance ofabnormal body composition, and to identify strategies to promote normal growth anddevelopment in pediatric recipients of alloHSCT.76

AcknowledgmentsSupported by the St. Baldrick’s Foundation, NIH (grants R01 HD040714, R01 DK060030, and K24 DK076808),and Clinical Translational Research Center (CTRC) (grant UL 1-RR-024134). The authors declare no conflicts ofinterest.

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Figure.Lean Mass per Height (LM-Ht) and Fat Mass per Height (FM-Ht) Z-scores in subjects withalloHSCT adjusted for height and age. Lean Mass* denotes further adjustment for FM-Ht Z-score.

Table 1

Subject Characteristics in AlloHSCT and Reference Participants

AlloHSCT Reference P-value

N 54 894

Age, yr 15.2 ± 4.8 11.8 ± 3.9 <0.001

Sex, n (% Male) 37 (69%) 429 (48%) 0.003

Race, n (% Black) 4 (7%) 385 (43%) <0.001

Pubertal Status, n (%)

Tanner stage 1 18 (33%) 316 (35%) NS

Tanner stage 2–3 11 (20%) 220 (25%) NS

Tanner stage 4–5 25 (46%) 349 (40%) NS

Height Z-Score*

Male −1.33 (−4.19 to 1.01) 0.20 (−2.07 to 2.60) <0.001

Female −1.29 (−3.12 to 1.95) 0.28 (−2.59 to 3.26) <0.001

BMI Z-Score*

Male 0.38 (−4.79 to 2.68) 0.42 (−3.09 to 2.99) NS

Female 0.28 (−2.40 to 1.82) 0.40 (−3.34 to 2.64) NS

NS, not significant

BMI, body mass index

Data are presented as mean + SD or median (range)

*Height and BMI Z-scores limited to subjects < 20 years of age because the national reference data are available through age 20.

Table 2

Disease and Treatment Characteristics in alloHSCT Participants

Age at Study Enrollment, yr 15 (5–26)

Age at Diagnosis, yr 6 (0.02–20)

Age at Transplant, yr 7 (0.08–21)

Interval Since Transplant, yr 7 (3–16)

Diagnosis, n (%)

Acute lymphoblastic leukemia 12 (22)

Acute myeloid leukemia 23 (42)

Chronic myeloid leukemia 6 (11)

Myelodysplastic syndrome 5 (9)

Juvenile myelomonocytic leukemia 5 (9)

Aplastic anemia 2 (4)

Bone marrow failure syndrome 1 (2)

Donor Source, n (%)

Related 28 (52)

Unrelated 25 (46)

Cord 1 (2)

TBI Conditioning Regimen, n (%) 38 (69)

Graft vs. Host Disease, n (%)

None 28 (52)

Acute 22 (85)

Chronic 16 (62)

Active at time of study visit 1 (4)

Treatment with Steroids since HSCT, N (%)

None 28 (52)

>12 months prior 25 (45)

Current 1 (2)

Endocrine Abnormalities, N (%)

Hypothyroid 20 (37)

Growth hormone deficient 16 (29)

Hypogonad (males) 6 (16)

Ovarian failure (females) 5 (50)

Data presented as median (range) or n (%)

Table 3

Lean Mass and Fat Mass Z-scores in AlloHSCT Subjects Compared with Healthy Reference Participants

Covariates β (95%) CI P-Value

FM-Ht Z-score*

Females Age and height 0.92 (0.42, 1.42) <0.001

Age, height and Tanner stage 1.07 (0.57, 1.56) <0.001

Males Age and height 1.39 (1.00, 1.78) <0.001

Age, height, and Tanner stage 1.33 (0.94, 1.73) <0.001

LM-Ht Z-score**

Females Age and height −0.99 (−1.50, −0.48) <0.001

Age, height and Tanner stage −0.81 (−1.32, −0.31) 0.002

Age, height, Tanner stage and FM-Ht Z −1.36 (−1.80, −0.92) <0.001

Males Age and height −0.62 (−1.02, −0.22) 0.002

Age, height and Tanner stage −0.55 (−0.96, −0.15) 0.007

Age, height, Tanner stage, and FM-Ht Z −1.19 (−1.56, −0.81) <0.001

*Fat mass for height Z-score

**Lean mass for height Z-score

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