Revised Proposal
Collaborative study between University of Glasgow Medical Faculty and King
Faisal Hospital and Research Centre, 30th September 2009
From Prof John J Reilly (jjr2y@clinmed.gla.ac.uk) and Fahad Aldhafiri
(fkdiet@hotmail.com)
Metabolic syndrome prevalence among childhood Acute
Lymphoblastic Leukaemia (ALL) patients after the end of treatment
Background
A fundamental dispute exists about the criteria to define metabolic syndrome
(MS) in children and adolescents. Nonetheless, most studies of both adults and
children generally define metabolic syndrome as the presence of at least one of the
following criteria: dyslipidaemia (low high-density lipoprotein cholesterol [HDL-C]
or high triglycerides [TG]), fasting glucose [FG] and/or insulin resistance [IR],
systolic [SBP] and/or diastolic [DBP] blood pressure, and finally obesity and/or
central adiposity measurements [1].
MS in childhood and adolescence is a growing concern. The prevalence of MS is
variable and is dependent on the diagnostic criteria and population, but it is increasing
in children and adolescents [2], and the availability of recently agreed International
Diabetes Federation (IDF) definitions of MS (defined below) has provided an
important opportunity to estimate prevalence of MS in a more standardised and
acceptable way[3].
ALL is the most common childhood malignancy, and prevalence of obesity and
other features of the MS are probably common both during and after therapy for ALL
[4]. Mertens et al. reported an increased risk of all-cause mortality, cardiovascularrelated mortality, cerebrovascular accidents, and chronic health conditions in longterm survivors of childhood ALL [5]. However, our literature search in 2009 has
found no large studies of prevalence of MS in survivors of ALL (no studies with
n>50), and no studies which used recent IDF criteria to define MS, and so a study of
the prevalence of MS in survivors is necessary.
Primary Scientific aim:
To estimate the prevalence of the Metabolic Syndrome in survivors of ALL in
first remission in King Faisal Hospital and Research centre (KFHRC).
Secondary Scientific aim:
To estimate the effect on prevalence estimates of MS when different definitions
were being used; (see the table 1).
Design and Methods
Step 1: Sample size and design considerations from Reilly & Aldhafiriri
discussions in 2009:
A cross –sectional study of MS in a fairly homogenous sample of approximately 70100 patients with ALL in first remission and who have reached the end of therapy is
intended.
Sample size is justified as this is an exploratory study, prevalence of MS or its
components is likely to be very high, and the sample size intended should be practical.
This would be a relatively large study. The largest study in this field to date had only
44 patients [6].
Step 2: check patient eligibility-undertaken by Fahad in collaboration with the local
clinical team.
Inclusions: Patients

Age 6 -18 years in first remission for ALL after the end of ALL treatment;
with standard and low risk ALL according to KFSH&RC/ department of paediatric
haematology oncology criteria defined as patient with precursor B-cell will be
considered standard risk only if all of the following :

Age > 1 year and < 10 year.

Initial WBC < 50 x 109 / L

DNA index ≥ 1.16 or ≤ 1.6

Lack of adverse cytogenetics/molecular genetic studies.
It should be emphasised 10 years old refers to the age at the time of
diagnosis. However, age range of this study (6-18 years) refers to the
age at the time of conducting this off therapy study
Exclusions-Patients

Who have relapsed at any stage.

Who have -or have had -a secondary malignancy.

Younger than 6, older than 18 at the time of this study.

With high risk ALL according to Rome/ NCI criteria as mentioned.

Who are being or have been treated for MS or related disease such as diabetes.
Step 3: Data Collection and Interpretation
Patient data: Collected and interpreted by Fahad with the local team.

Age, gender

Fasting bloods for definition of blood based components of MS (see below)

Patient weight to 0.1kg

Patient height to 0.1cm

Waist circumference (WC)

BMI; which is defined as weight in Kg divided by height in m (square)

BMI z score : the calculation is done using a skewness parameter (L), mean
(M) and standard deviation (S) , which are available on US CDC website
www.cdc.gov, and is as follows: BMI-Z score= [(x/m)L -1)/ (L*S)}.
www.cdc.gov/growthcharts) as shown on the appendix 3. BMI-z score > 2.0
indicates for Obesity.

DEXA measured body fatness

Time since diagnosis

Time since end of therapy

Summary of ALL therapeutic regimes (ie which protocol was used and which
arm of the protocol as appropriate).

Main definition of MS- MS will be defined as International Diabetes
federation (IDF) which is modified for paediatric use in the age range 10-16
years; for those age 6-9 the number of components of metabolic syndrome
components (see appendix 1) and we will also calculate MS prevalence by the
other definitions too (see appendix 2).
Step 4: Data interpretation
Prevalence is simply the percentage of eligible patients with MS in the total sample.
Means and their 95% confidence intervals were calculated for each variable. All
analysis will performed using SPSS version 14.0. P< 0.05 will be considered
statistically significant.
Measurements to be made:
The following measures would be required on one occasion from each patient:
 clinical measurement:

Body composition using Dual Energy X Ray Absorptiometry (DXA) that will
be conducted and interpreted by Radiologist from nuclear medicine services.
A standard whole-body DXA examination included total body and three
regional measurements of trunk (chest, abdomen, and pelvis), arms, and legs
to analyze body composition according to a three-compartment model: fat
mass, lean tissue, and bone mineral content.

Height to 0.1cm, weight to 0.1kg in hospital gown, both measured by the same
trained observer on calibrated equipment.

Waist circumference (WC); the best method for measuring WC is from
horizontal plane 4 cm above the umbilicus (10).

Blood pressure measured in triplicate at one occasion, preferably by the same
trained observer (Diastolic, Systolic) by applied the right cuff position.
 Biochemistry measurements:
Fasting bloods analysed for:

lipid profile (Triglycerides, HDL-C, LDL-C, Total Cholesterol)

glucose

insulin

liver enzymes
Ethical consideration:
This study will be conducted according to Helsinki ethical and standard ethical
practice of medicine in kingdom of Saudi Arabia as approved and adapted by the
Research Advisory Council (RAC) in KFHRC.
Saudi Investigators

Dr. Abdullah Alnasser: the principal investigator

Dr. Yasmin Altwejri : Co-investigator

Mr. Fahad Aldhafiri: Co-investigator

Mrs Hanan Almutairi: Co-investigator
All above researchers will share in data collections, recruit and measure (Blood
Pressure, waist conference, Height and weight) the subjects. However, the blood will
be withdrawn by KFSHRC nurses and it will be analysed at KFSHRC laboratories. As
well as body composition will be examined by KFSHRC technicians using DXA
device.
Timescale
We would aim for completion of all data collection on the ALL patients by the
beginning of 2010. Summary data, data interpretation, and dissemination would
follow from Glasgow in the second half of 2010.
Practicalities and Issues for Discussion

Data required could be obtained from routinely collected examinations if
appropriate, or may require additional measures.

Saudi Ethics approval is required for these studies.

The proposals are suggested to be a full collaboration (including authorship)
between the UK and Saudi partners.

Input from Saudi partners would be valued on any issue raised by these
proposals.
Outcomes and Dissemination

1 paper based on the prevalence of Metabolic Syndrome amongst survivors of
Acute Lymphoblastic Leukaemia in KFHRC; submitted to a nutritional,
paediatric or oncology journal.

1 PhD thesis chapter for Fahad Aldhafiri, and a good PhD submitted by end
2011.

Establishment of a longer-term collaborative research link between University
of Glasgow and King Faisal Hospital researchers.
References
1. Saland, J.M., Update on the metabolic syndrome in children. Current Opinion in
Pediatrics, 2007. 19(2): p. 183.
2. Grundy, S.M., et al., Definition of metabolic syndrome report of the National
Heart, Lung, and Blood Institute/American Heart Association Conference on
scientific issues related to definition. 2004, Am Heart Assoc. p. 433-438.
3. Zimmet, P., et al., The metabolic syndrome in children and adolescents. The
Lancet, 2007. 369(9579): p. 2059-2061.
4. Reilly, J.J., Obesity during and after Treatment for Childhood Cancer. Endo Dev,
2009. 15: p. 40-58.
5. Mertens, A.C., et al., Late mortality experience in five-year survivors of childhood
and adolescent cancer: the Childhood Cancer Survivor Study. Journal of
Clinical Oncology, 2001. 19(13): p. 3163-3172.
6. Oeffinger, K.C., et al., Cardiovascular risk factors in young adult survivors of
childhood acute lymphoblastic leukemia. Journal of Pediatric Hematology Oncology,
2001. 23(7): p. 424.
7. Reilly JJ et al . Prevalence of protein energy malnutrition at diagnosis in children
treated for ALL. J pediatr Gastroenterol Nutr 1999; 29: 194-197.
8. J Weir, JJ Reilly et al. No evidence for an effect of nutritional status on clinical
outcome in childhood ALL. J Pediatr Hematol Oncol 1998; 20: 534-538.
9. Reilly JJ et al. Premature adiposity rebound in children treated for ALL. J Clin
Endocrinol Metab 2001; 86: 2775-2778.
10. Rudolf M C, et al., What is the best way to measure waist circumference?.
International Journal Of Paediatric obesity, 2007. 2: 58- 61
(2007)
11. Sorof J, et. Al., Obesity Hypertension in Children A Problem of Epidemic
Proportions. American Heart Association, . 2002;40
12. Boyd G, et. al., Effect of Obesity and High Blood Pressure on Plasma Lipid
Levels in Children and Adolescents. the American Academy of Pediatrics.,
2005; 116;442-446
13. Golley, R.K., et al., Comparison of metabolic syndrome prevalence using six
different definitions in overweight pre-pubertal children enrolled in a weight
management study. International Journal of Obesity, 2006. 30(5): p. 853-860.
Appendixes
Appendix 1
Definitions of metabolic syndrome components and metabolic syndrome in 6-9 year
olds
 Age 6 to 9 years:
The number of metabolic syndrome components will be summarised for each
patient. Prevalence will be expressed as the percentage of the sample with 1, 2, and 3
or more components of the metabolic syndrome. Metabolic syndrome components
rather than metabolic syndrome are defined in 6-10 year olds and the criteria defining
each component are listed below:

Central obesity (waist circumference ≥ 90th percentile relative to UK
reference) see appendix 4.

Obesity (BMI > 95th percentile for age and sex) see appendix 3.

High blood pressure, defined as Patients with average systolic or Diastolic
≥95th percentile (see appendix 5).

HDL cholesterol defined as < 40 mg / dl, (1.03 mmol/L)

Triglycerides defined as > 150 mg/ d, (1・7 mmol/L)

Fasting glucose defined as
> 140 mg/dL (7.7 mmol/ L)
IDF defi nition of at-risk group and of metabolic
syndrome in children and adolescents (3) in those Age 10 to <16 years
• Obesity ≥90th percentile as assessed by waist circumference
• Triglycerides ≥ 1・7 mmol/L ( ≥150 mg/dl)
• HDL-cholesterol <1.03 mmol/L (_< 40 mg/dl)
• Blood pressure ≥130 mm Hg systolic or ≥85 mm Hg
diastolic
• Glucose ≥5・6 mmol/L (≥ 100 mg/dl)
Appendix 2
(modified from Golley and Zimmet studies [3,13] )
Indicator criteria[a]
Definition of metabolic
syndrome
Glucose
(mmol/l)
Triglycerides
(mmol/l)
HDL-C
(mmol/l)
Systolic
blood
pressure
(mmHg)
BMI
centile
Waist
circumfere
nce (cm)
Insulin
(pmol/l)
Adult European
Group for the Study
of Insulin
Resistance (EGIR†)
(Balkau and
Charles)[b]
Adult US National
Cholesterol
Education Program
(NCEP‡) (NIH)[e]
Lambert child
modified (Lambert et
al.)[b]
6.1
2.0 [c]
1.0 [c]
140
___
M [d]: 94
F [d]: 80
51
6.1
1.7
1.0
130
___
M: 102
F: 88
___
6.1-7.9
1.8
0.8
P-95%
height
P-85%
___
Adult EGIR modified
[b]
6.1-7.9
1.8
0.8
P-95%
height
___
P-91%
Adult NCEP modified
[e]
6.1-7.9
1.8
0.8
P-95%
height
___
P-91%
M:
35.0
F:
40.6
M:
35.0
F:
40.6
___
5・6
1・7
1・03
130
___
P-90%
___
International
Diabetes Federation
[a] Greater than or equal to value except HDL-C for which less than or equal
to value. [b] MS present if insulin and any other two indicators meet the
criterion. [c] High triglyceride and/or low HDL-C. [d] M= males, F= females. [e]
MS present if any three indicators meet the criterion.
† European Group for the Study of Insulin Resistance
‡US National Cholesterol Education Program
Appendix 3:
Appendix 3 cont..
Appendix 5:
Appendix 5 conti..
Appendix 5 conti..
Appendix 5 conti..