BMJ Open€¦ · For peer review only Recruitment feasibility to ascertain endocrine and metabolic...

For peer review only

Recruitment feasibility to ascertain endocrine and metabolic health among survivors of childhood brain tumors: A report

from the Canadian study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE)

Journal: BMJ Open

Manuscript ID: bmjopen-2014-005295

Article Type: Research

Date Submitted by the Author: 19-Mar-2014

Complete List of Authors: Samaan, M. Constantine; McMaster University, Department of Pediatrics, Division of Pediatric Endocrinology Scheinemann, Katrin; University Children's Hospital, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Department of Paediatric Hematology/Oncology Burrow, Sarah; McMaster University, Division of Pediatric Orthopedics, Department of pediatric Surgery Dillenburg, Rejane; McMaster University, Department of Paediatrics, Division of Cardiology Barr, Ronald; McMaster University, Department of Paediatrics, Division of

Hematology/Oncology Wang, Kuan-Wen; McMaster University, Department of Paediatrics, Division of Pediatric Endocrinology Valencia, Marlie; McMaster University, Department of Paediatrics, Division of Pediatric Endocrinology Thabane, Lehana; McMaster University, Department of Paediatrics

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Diabetes and endocrinology, Patient-centred medicine, Research methods

Keywords: Paediatric endocrinology < DIABETES & ENDOCRINOLOGY, Paediatric oncology < ONCOLOGY, IMMUNOLOGY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Recruitment feasibility to ascertain endocrine and metabolic health among survivors of

childhood brain tumors: A report from the Canadian study of Determinants of

Endometabolic Health in ChIlDrEn (CanDECIDE)

M. Constantine Samaan1,2 *

, Katrin Scheinemann1,3,4

, Sarah Burrow5, Rejane F.

Dillenburg1,6

, Ronald Barr1,3

, Kuan-Wen Wang1,2

, Marlie Valencia1,2

, Lehana

Thabane1,7,8,9,10

M. Constantine Samaan 1,2 *

: [email protected]

Katrin Scheinemann1,3,4

: [email protected]

Sarah Burrow5: [email protected]

Rejane Dillenburg1,6

: [email protected]

Ronald Barr1,3

: [email protected]

K.W. Wang1,2

: [email protected]

Marlie Valencia1,2

: [email protected]

Lehana Thabane1,7,8,9,10

: [email protected]

1Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada

2Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario,

Canada 3Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton,

Ontario, Canada 4Department of Paediatric Hematology/Oncology, University Children's Hospital, Albert-

Schweitzer-Campus 1, Building A1, 48149 Münster, Germany 5Division of Pediatric Orthopedics, Department of pediatric Surgery, McMaster

University, Hamilton, Ontario, Canada 6Division of Pediatric Cardiology, McMaster Children’s Hospital, Hamilton, Ontario,

Canada 7

Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton,

Ontario, Canada 8Department of

Anesthesia, McMaster University, Hamilton, Ontario, Canada

9Centre for Evaluation of Medicines, Hamilton, ON, Canada

10Biostatistics unit, St Joseph’s Healthcare-Hamilton, Hamilton, Ontario, Canada

* Corresponding author: M. Constantine Samaan

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Abstract:

Objectives: The aim of this study was to test the feasibility of recruitment and

performance of study procedures of the Canadian Study of Determinants of

Endometabolic Health in ChIlDrEn (CanDECIDE) study, which was designed to assess

the determinants of endocrine and metabolic health in survivors of childhood brain

tumors.

Setting: A single pediatric tertiary care center in Hamilton, Ontario, Canada

Participants: We included boys and girls, aged 5 years and older, who were lean (BMI

below 85th

centile for age and gender) or overweight/obese (BMI 85th

centile or above for

age and gender). We excluded children on steroids or immunosuppressant therapy,

smokers and those who had an active infection for the 2 weeks prior to

participation. We approached 210 potential participants, and 112 (53%) agreed to

participate. Of the latter group, 30 (26.8%) have already completed the study visit over 7

months.

Outcomes: Feasibility targets were: recruitment rate of at least 50%, the consenting of

80% to provide biological samples, 90% completing all questionnaires, and the ability to

process biological samples for at least 80% of participants.

Results: Our recruitment rate was 26.8% (30/112), and all those who consented agreed to

fast, provide biological samples and complete the questionnaires. Sample collection was

successful in 97% (29/30) of participants and laboratory procedures were feasible in

100% of collected samples. We also tested resources required for the conduct of the full

study including personnel, space, laboratory equipment and procedures and determined

that they are all feasible.

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Conclusions: Recruitment and consenting of patients for the CanDECIDE study may be

feasible. However, we are considering prolonging recruitment duration and collaboration

with other centers to meet recruitment targets due to lower than expected recruitment

rate. Completion of questionnaires and implementation sample processing protocols are

feasible.

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Strengths:

• We tested the feasibility of the CanDECIDE study that is examining the

Endometabolic health of survivors of childhood brain tumors

• We found that the study is feasible, with consent rates of 97%, and laboratory

procedures were achievable in all cases.

Limitations:

• Our recruitment rate was 26.8% (30/112), which is lower than the predicted rate

of 50%

• We are proceeding with the full study with prolongation of the duration of

recruitment and consideration for inclusion of other centers to meet study targets

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Introduction:

Advances in brain tumor diagnosis and therapy have resulted in high survival rates in

children over the past three decades, yet this has been coupled with higher premature

mortality, and considerable morbidity, including obesity and diabetes, in survivors1-6

. The

factors that contribute to the metabolic problems in survivors of childhood brain tumors

(SCBT) include hypothalamic damage7-9

, deficiency of pituitary hormones7 8 10

, reduced

mobility and physical activity levels11-14

, reduced exercise capacity and motivation15 16

, sleep

disturbances17

, visual compromise, imbalance and pain,18 19

and medication use (e.g.

steroids, antidepressants)20

. Defining the mechanisms of obesity and diabetes in survivors

will help design treatment and prevention strategies that will lead to improved lifespan and

quality of life.

Over the past few years, new insights into the role of the immune system in obesity and

cancer have been described. Tumor cells interact with immune cells to create the tumor

microenvironment that regulates tumor cell growth, metastasis and metabolism21 22

. One of

the immune cells involved in this interaction is the monocyte, which migrates to tumors and

neighboring areas and differentiates to tumor-associated macrophages21

. While these cells

have been detected in brain tumors, their role in systemic inflammation, obesity and diabetes

in survivors is unknown23 24

.

Obesity is characterized by both local and systemic inflammatory responses25 26

.

Macrophages are present within metabolic organs and secrete cytokines that propagate local

inflammation27-31

, and these cytokines can enter the circulation and cause systemic

inflammation32-35

. In turn inflammation causes insulin resistance and, if the latter is

untreated, will lead to type 2 diabetes.

There is very limited evidence available regarding systemic inflammation in SCBT. In a

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study including a small group of brain tumor survivors (n=19), SCBT had elevation of the

inflammatory marker C-Reactive Protein (CRP)36

; but this is not a satisfactory marker of

inflammation in children37 38

. In the general pediatric population with no history of cancer,

our group39

and others have reported some of the cytokines associated with childhood

obesity.40-45

In order to establish if obese SCBT have enhanced systemic inflammation compared to lean

survivors and non-cancer controls, and to identify the potential lifestyle factors that may

drive this response, the Canadian Study of Determinants of Endometabolic Health in

ChIlDrEn (CanDECIDE study) was initiated; the protocol for which has already been

published.46

The aim of this pilot study was to evaluate study processes and procedures to

determine the feasibility of the full study.

Objectives: The primary aim of this pilot study was to test the feasibility of the

CanDECIDE study including recruitment rates, data collection forms’ content and design,

data completion, time needed to interview participants, feasibility of fasting and biological

sample collection, and testing of laboratory procedures to process samples including time,

equipment, personnel, consumables and additional resources needed.

Methods:

Setting & participants. This study was initiated at McMaster Children’s Hospital, a

tertiary pediatric center in Hamilton, Ontario, Canada. The Hamilton Integrated

Research Ethics Board approved the study. SCBT were recruited from the neurooncology

clinic at the Hospital, and description of the setting has been published previously.46

The

control group included children with healed fractures, minor scoliosis, or those with a

history of syncope with no structural cardiac or conduction defects (recruited from clinics at

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the Hospital), along with healthy children recruited from the local community.

Inclusion criteria: We included boys and girls, aged 5 years and older, who were lean

(BMI below 85th


centile or above

for age and gender), and for SCBT we included those who had completed tumor therapy at

least 6 months earlier.

Exclusion criteria: We excluded children on steroids or immunosuppressant therapy,

smokers and those who had an active infection for the 2 weeks prior to participation.46

Data collection & instruments: We used standardized tools to collect data comprising

diet47 48

, physical activity49

, sleep50

, stress51

, and neighborhood walkability52

. Additional

data collected include age, sex, ethnicity, education, profession, social history, medical

history, medications, illicit drug use, smoking, birth history, menstrual history in girls, and

family history. We designed a Case Report Form specifically for the study, and collected

data including diagnosis, location of tumor, treatment(s), comorbidities, height, weight,

waist circumference, hip circumference, BMI, blood pressure, heart rate, and grip strength46

.

Adiposity was measured using bioelectrical impedance with Tanita scale (Tanita

Corporation)53

for those less than 18 years of age, and the InBody520 body composition

analyzer (GE Healthcare) for those 18 years or older54

.

Sample collection and laboratory processing:

All blood and urine samples were collected in the fasting state. Fasting was started from

midnight for at least 8 hours. Due to the age group the study is dealing with, children were

allowed to drink water but sugary drinks and food were not allowed until sample collection

was completed. Experienced pediatric phlebotomists and/or researchers collected blood

samples, and samples were processed within 2 hours of collection. For saliva, participants

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either gave fasting samples, or had breakfast and then waited for at least 30 minutes before

providing the samples.

Feasibility of study procedures: the primary outcome for this study was to evaluate the

feasibility of the full CanDECIDE study. Specifically, we examined the following:

1- The feasibility of recruitment by calculating the number of subjects approached and rates

of acceptance and consenting

2- Case report form and questionnaire completion rates

3- The evaluation of resources needed to conduct the study, including personnel, space, and

laboratory equipment

4- The feasibility of fasting and biological sample collection: The latter was noted by

agreement to provide blood, urine, and saliva samples

5- The feasibility of analytes’ isolation in the laboratory, including monocytes, serum,

plasma, buffy coat, urine, and saliva.

Feasibility criteria:

In this feasibility study, we designed a priori criteria for a feasible study which included the

following conditions: a recruitment rate of at least 50%, the consenting of 80% to provide

biological samples, 90% completion rate of all questionnaires, and the ability to isolate

monocytes, serum, plasma, buffy coat, urine and saliva in at least 80% of participants. We

also evaluated the resources needed to perform the study, including personnel, space and

laboratory utilization for sample processing.

Statistical analysis:

The primary reason for this pilot study was to establish feasibility. The target sample size

was n=30 which was determined primarily based on feasibility considerations to test

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procedures for the full study where we plan to recruit 300 participants. The

sociodemographic and outcome variables are reported using descriptive measures including

the mean (SD) for continuous variables and number (percent) for categorical variables. The

study data were managed using Research Electronic Data Capture (REDCap) tools hosted at

McMaster University.55

The analysis of feasibility outcomes was descriptive in nature, with

the results expressed as percentages and feasibility assessed against the corresponding

targets. The data were analyzed using SPSS version 22.0 (Armonk, NY: IBM Corp).

Results:

Participant recruitment rate:

Over the period from November 2012-July 2013, 210 potential participants agreed to be

approached by the research team after their care provider asked for permission; in the case

of participants from the community, they contacted the study team directly having heard

about the study. Of those subjects, 112 (53%) agreed to participate including 1 from the

community, 23 from neurooncology, 11 from cardiology, and 77 from orthopedic clinics.

There were no major differences in recruitment rates between neurooncology and other

clinics. Subject who did not wish to participate in the study (n=98) cited different reasons

for their decision including travel distance and transportation (n=26), discomfort with blood

sampling (n=24), no interest in research participation (n=32), unavailability to attend

research clinic visits due to scheduling conflicts (n=13), and other reasons (n=3). For this

pilot study, we completed the recruitment of 30 subjects within the above period, resulting

in a recruitment rate of 26.8% (Figure 1).

Participant Demographics:

As shown in Table 1, of the 30 subjects recruited 12 (n=4 female) were in the SCBT group

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and 18 (n=12 female) in the control group. The majority of participants in both groups

(83%) were Caucasian Europeans. In the SCBT group, the average age was 14.3±4.6 years,

and 33% of SCBT were overweight/obese. One third had received radiotherapy, 31%

chemotherapy, 83% had surgery and the majority received short-term steroids in

perioperative period. The tumor types included 5 astrocytomas, 5 medulloblastomas, and 2

other types. The mean (SD) age in the non-cancer comparison group was 12.6 (2.7) years, of

whom 39% were overweight/obese.

The availability of clinical space was paramount to allow study visits to take place. We did

utilize clinic space consisting of 5 clinic rooms within the Hospital space, and we used 4

rooms to interview participants and one room was set up for blood collection.

All those who agreed to participate and signed consent forms agreed to provide biological

samples. We did offer all participants the use of topical anesthetic creams or patches for

phlebotomy, and only a few wanted to use them. Once collected, the samples were then

taken to the research laboratory for further processing. In one patient it was not possible to

get blood samples, giving a sample collection rate of 97%. The equipment utilization in the

laboratory was appropriate for the workload of this study, and 4 research students were

trained in the laboratory study procedures and were responsible for sample processing,

storage and cataloguing.

Biological sample isolation and processing in the laboratory:

Monocytes: We isolated monocytes from whole blood collected into a 15ml Corning tube

containing 150µl of 100mM EDTA. The samples were layered on Polymorphprep

separation gradient, and samples centrifuged at 650g for 35 minutes at room temperature

with brakes off. To isolate monocytes, we removed the mononuclear cell layer from the

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gradient and used EasySep™ magnetic bead Human Monocyte Enrichment Kit without

CD16 depletion (Stemcell Technologies) as per manufacturer’s instructions, to isolate

monocytes within 2 hours of sample collection.

Serum: Fasting serum samples were collected from clotted blood after centrifugation for 15

minutes at 1,500g at room temperature. Samples were aliquoted and stored at -80 °C.

Plasma: Fasting plasma samples were collected by centrifuging EDTA-treated blood at

1,500g for 15 minutes at room temperature. Samples were aliquoted and stored at -80 °C

until further use.

Buffy coat: EDTA-treated blood samples were centrifuged at 1,500g for 15 minutes at room

temperature, and the buffy coat layer was collected. Samples were stored at -80 °C until

further use.

Urine: Fasting urine samples were collected in 90 ml urine containers, and aliquoted and

frozen at -80 °C.

Saliva: Saliva samples were collected either while the participants were fasting or at least 30

minutes after food or drink. Samples were collected using Oragene-DNA collection kits

(DNA Genotec Inc., Ontario, Canada), and stored at room temperature until further use.

Feasibility results:

In this study, we approached potential participants over a 7-month period. The number of

those who agreed to participate was 97 (51%). So far, we have completed the study on 30

subjects giving a recruitment rate of 31%. This is lower that our target of 50% recruitment

rate.

Case report form completion was done in 100% of cases; we used a system by which the

first researcher who interviews the participant would handover the questionnaires to another

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researcher who checks all forms and completes any missing data while participants are in

clinic. In addition, the forms were audited within 1 week of study completion, and families

and participants contacted to clarify or add any missing information. The completion of all

study procedures including consenting, completion of questionnaires and provision of

biological samples took 70-90 minutes.

In relation to clinic staffing, we had 8 research students involved in the recruitment of

participants, and this number was judged adequate to deal with the workload, based on the

need to cover clinics during the week for recruitment and staffing the research clinic visits.

These students were provided with specific training to approach potential participants,

obtaining consent, scheduling of clinic visits, conducting study procedures including

anthropometric and other measures, and the administration of study questionnaires. In

addition, three students from the group who were not involved in study recruitment or

procedures were responsible for auditing the questionnaires and completion of data

collection forms to ensure high quality of data. Furthermore, two other students were

involved in data entry into REDCap database.

The techniques used to isolate the study analytes proved to be feasible. Monocyte isolation

yielded excellent results in 90% of cases; in 3 participants, the gradient centrifugation did

not separate the cells accurately so no sample could be retrieved. Serum samples from 2

participants showed evidence of hemolysis and were labeled as such until further processing

is undertaken to determine if this has interfered with sample quality. One saliva sample had

food particles, and in another one the preservative fluid leaked after sample collection, and

these samples will be excluded from further analysis.

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Discussion:

This feasibility study tested the clinical and laboratory procedures for the CanDECIDE

study, a cohort study designed to determine the factors affecting the endocrine and

metabolic outcomes in SCBT and comparing them to participants with no history of cancer.

Using the initial 30 participants’ data, we demonstrate the relatively lower rates of

recruitment than anticipated initially, adequate responses to questionnaires, and satisfactory

consent rates to provide biological samples. We also demonstrate the feasibility of

additional study procedures including consenting, data collection, data entry, data analysis,

and laboratory sample processing protocols and techniques.

Study strengths:

One of the significant strengths of this study was the establishment of collaborations among

several clinical teams within the Hospital to recruit study participants. The alliance created

by this collaboration demonstrates the feasibility of the expansion of this platform to

conduct the full study.

In addition, the creation of robust data collection tools, body measurement protocols, and

standardized platforms for data handling has allowed the study group to collect high quality

data and demonstrated the feasibility of this structure in the full study with no modifications.

Lessons learned to inform the design of CanDECIDE study:

One of the limitations we faced during this pilot phase was related to recruitment targets.

We envisaged initially recruiting 300 participants over 2 years; this was based on 50%

projected recruitment rate, and seeing around 3 patients per week. The recruitment rate for

the feasibility study was 26.8%, as scheduling these patients to clinic visits was taking

longer than we had anticipated at first. This was because sometimes the team could not use

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the phone number or e-mail address provided to contact the family, or scheduling conflicts

for families prevented them from attending study visits and they needed to reschedule. To

address this, our next step is to prolong the recruitment phase to 4 years to try to address this

issue. In addition, we had to broaden the inclusion of other types of brain tumors, as we

were focusing only on astrocytomas, medulloblastomas and ependymomas. The caveat to

this is increased heterogeneity of the samples, which may then require a larger sample size

to achieve sufficient power to detect meaningful differences in inflammatory marker levels.

One possible avenue that may shorten the recruitment duration and maintain homogeneity of

the sample is collaboration with other centers caring for SCBT. We have already started

discussions with other neurooncology centers within Canada and abroad, and this approach

may help circumvent the issue of recruitment rates.

The one question that remains unanswered is the retention rate of participants in the full

study that will run for 10 years, especially the non-brain tumor group. For the SCBT group,

we have a unique setting in our Hospital whereby children and adults are followed in the

same clinic, which allows us to maintain high rates of longitudinal follow-up.

In order to enhance retention in the study, we are planning to have newsletters sent to

participants annually via e-mail and mail; we are also planning annual study information

days in which participants and their families are invited to engage the research team, receive

study updates, and address any questions about various aspects of the study.

The study may also be prone to several sources of bias. Selection bias may occur if the

choice of participants is not representative of the general population, as our comparison

group is mostly composed of children attending other clinics in the Hospital. Our approach

to minimize selection bias is to ensure that recruited participants are free from disease and

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have a self-limiting or stable condition. For example, participants recruited from the

orthopedic clinic are seen in research study visits after their fractures are healed; our recruits

from the cardiology clinic were assessed for cardiac defects and only included if they had a

structurally normal heart and no conduction defects. Recruits from the community were

again assessed to determine the absence of disease and medication use that may affect their

immune-metabolic status before consenting.

Recall bias may arise when questions are asked about events that occurred a long time ago

e.g. family history details of grandparents. For ACBT, all clinical data regarding care have

been obtained from clinical notes from a previous study we conducted thus minimizing this

form of bias.

Another form of bias we need to guard against is social desirability bias, which arises when

subjects offer “healthier” answers to the researcher. One of the ways we circumvented this

was by using structured data collection tools and laboratory data (e.g. looking at levels of

fasting glucose or fasting lipid levels) to ensure we can account for this issue.

Conclusions:

In summary, we have tested the feasibility of the CanDECIDE study, and found that many

study procedures are accomplishable. However we will need to prolong the recruitment

phase, broaden tumor types included in the study, and consider incorporating other centers

into the study. In addition, we validated our laboratory procedures for sample processing

and we are currently preparing to proceed with the full study with implementation of the

changes suggested.

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Acknowledgements:

We would like to acknowledge the study participants and their families for participating

in the study. We also would like to acknowledge the McMaster University students who

helped with study visit conduct and laboratory procedures: Amrita Amarnaney, Pauline

Chang, Connie Cheung, Jiyeh Joo, Ishan Aditya, Nicola Sahar, Ameir Makar, Calvin

Tang, Glara Rhee, Brittany Watson, and Madeleine Bondy.

This study was partly funded by Joshua’s Journey (Hamilton Health Sciences

Foundation) Neurooncology fund. MCS is funded by New Investigator Fund grant from

Hamilton Health Sciences.

Contributorship Statement:

MCS conceived the study question and generated the hypotheses.

MCS, LT, RD, RDB, SB and KS finalized the study design. MCS, KWW, MV and LT

completed the statistical analysis plans. MCS, RD, SB, RDB and KS contributed to the

definition of study cohorts, inclusion and exclusion criteria, recruitment plan and

study logistics including space and resource allocation.

KWW and MV were involved in recruitment, consenting, administration of

questionnaires, anthropometric measures, data collation and analysis.

MCS wrote the manuscript and all authors reviewed the current version.

Competing Interests: None

Data Sharing Statement: The additional data include additional clinical data based

on the questionnaires reported in our protocol paper including diet, physical

activity, sleep, stress, and build environment. This paper is focused on reporting

feasibility, and the data will be included in the full study for analysis. As the data is

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still not fully analyzed and data collection is ongoing, the data will be available at the

end of the study.

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1. Nader PR, O'Brien M, Houts R, Bradley R, Belsky J, Crosnoe R, et al. Identifying risk

for obesity in early childhood. Pediatrics 2006;118(3):e594-601.

2. Freedman DS, Mei Z, Srinivasan SR, Berenson GS, Dietz WH. Cardiovascular risk

factors and excess adiposity among overweight children and adolescents: the

Bogalusa Heart Study. J Pediatr 2007;150(1):12-17 e2.

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36. Lipshultz SE, Landy DC, Lopez-Mitnik G, Lipsitz SR, Hinkle AS, Constine LS, et al.

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37. Skinner AC, Steiner MJ, Henderson FW, Perrin EM. Multiple Markers of

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39. Samaan MC, Obeid J, Nguyen T, Thabane L, Timmons BW. Chemokine (C-C motif)

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grade inflammation in juvenile obesity and type 1 diabetes associated with

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45. Calcaterra V, De Amici M, Klersy C, Torre C, Brizzi V, Scaglia F, et al. Adiponectin,

IL-10 and metabolic syndrome in obese children and adolescents. Acta

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46. Samaan MC, Thabane L, Burrow S, Dillenburg RF, Scheinemann K. Canadian

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study): a cohort study protocol examining the mechanisms of obesity in

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https://regepi.bwh.harvard.edu/health/KIDS/files/03.%202012%20Youth%2

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51. Faulstich ME, Carey MP, Ruggiero L, Enyart P, Gresham F. Assessment of

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52. Brownson RC, Chang JJ, Eyler AA, Ainsworth BE, Kirtland KA, Saelens BE, et al.

Measuring the environment for friendliness toward physical activity: a

comparison of the reliability of 3 questionnaires. American journal of public

health 2004;94(3):473-83.

53. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PMA, Wilding JPH. Obstructive

sleep apnoea is independently associated with an increased prevalence of

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54. Yao M, Ludwa I, Corbett L, Klentrou P, Bonsu P, Gammage K, et al. Bone speed of

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adolescents. Pediatric exercise science 2011;23(1).

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Figure 1: Flow diagram for CanDECIDE study recruitment

Table1: Baseline Characteristics of participants

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Figure 1

Par cipants approached for recruitment in

clinics or in community

(n=210)

Subjects mee ng the eligibility criteria for

par cipa on in the study

(n=210)

Subjects agreeing to par cipate in the

study

(n=112)

Subjects refusing to par cipate in

the study

(n=98)

Subjects who completed recruitment so

far

(n=30)

Reasons for refusal

- Transporta on/distance (n=26)

- Blood sampling concerns (n=24)

- No interest in par cipa on (n=32)

- Schedule conflicts (n=13)

- Other (n=3)

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Variable

Control

(n=18)

SCBT

(n=12)

Mean SD Mean SD

Age (years) 12.6 2.7 14.3 4.6

Height (cm) 156.7 11.6 151.5 23.6

Weight (kg) 54.0 15.0 52.5 24.0

BMI(kg/m2) 21.7 4.6 21.8 6.7

% Overweight/obesity 39.0% 33.0%

% Fat mass 24.1 8.6 23.3 13.0

Waist circumference (cm) 67.3 16.4 70.4 22.1

Hip circumference (cm) 83.5 16.3 82.1 23.2

Heart rate (bpm) 78.9 9.5 85.5 10.6

Systolic BP (mmHg) 107.9 9.5 99.3 11.6

Diastolic BP (mmHg) 65.1 8.1 64.2 7.8

Birth weight (g) 3,550 598 3,611 657

SCBT=Survivors of childhood brain tumors

Control=Participants with no history of cancer

SD=Standard deviation

BMI=Body mass index

BP=Blood pressure

Table 1

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Recruitment feasibility to a cohort study of endocrine and metabolic health among survivors of childhood brain

tumors: A report from the Canadian study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE)

Journal: BMJ Open

Manuscript ID: bmjopen-2014-005295.R1

Article Type: Research

Date Submitted by the Author: 05-Jun-2014

Complete List of Authors: Samaan, M. Constantine; McMaster University, Department of Pediatrics, Division of Pediatric Endocrinology Scheinemann, Katrin; University Children's Hospital, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Department of Paediatric Hematology/Oncology Burrow, Sarah; McMaster University, Division of Pediatric Orthopedics, Department of pediatric Surgery Dillenburg, Rejane; McMaster University, Department of Paediatrics, Division of Cardiology Barr, Ronald; McMaster University, Department of Paediatrics, Division of

Hematology/Oncology Wang, Kuan-Wen; McMaster University, Department of Paediatrics, Division of Pediatric Endocrinology Valencia, Marlie; McMaster University, Department of Paediatrics, Division of Pediatric Endocrinology Thabane, Lehana; McMaster University, Department of Paediatrics

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Diabetes and endocrinology, Patient-centred medicine, Research methods, Oncology, Paediatrics

Keywords: Paediatric endocrinology < DIABETES & ENDOCRINOLOGY, Paediatric oncology < ONCOLOGY, Immunology < TROPICAL MEDICINE


BMJ Open on June 11, 2020 by guest. P

rotected by copyright.http://bm

jopen.bmj.com

/B

MJ O

pen: first published as 10.1136/bmjopen-2014-005295 on 26 June 2014. D

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1

Recruitment feasibility to a cohort study of endocrine and metabolic health among

survivors of childhood brain tumors: A report from the Canadian study of Determinants

of Endometabolic Health in ChIlDrEn (CanDECIDE)




Dillenburg1,6

, Ronald Barr1,3

, Kuan-Wen Wang1,2

, Marlie Valencia1,2

, Lehana

Thabane1,7,8,9,10


: [email protected]


: [email protected]



: [email protected]

Ronald Barr1,3

: [email protected]

K.W. Wang1,2

: [email protected]

Marlie Valencia1,2

: [email protected]

Lehana Thabane1,7,8,9,10

: [email protected]

1Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada

2Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario,





Canada 7

Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton,

Ontario, Canada 8Department of

Anesthesia, McMaster University, Hamilton, Ontario, Canada

9Centre for Evaluation of Medicines, Hamilton, ON, Canada

10Biostatistics unit, St Joseph’s Healthcare-Hamilton, Hamilton, Ontario, Canada


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Abstract:





tumors.



below 85th





participation.

Outcomes: Feasibility targets included recruitment rate of at least 50%, the consenting of

80% of participants to provide biological samples, 90% questionnaire completion rate,

and the ability to process biological samples from at least 80% of participants.

Results: We approached 210 potential participants, and of the 112 (53%) who agreed to

participate, 30 (26.8%) completed the study visit over 7 months. All participants agreed

to fast, provide biological samples and complete the questionnaires. Sample collection

was successful in 97% (29/30) of participants and laboratory procedures were feasible in

100% of collected samples. We also tested resources required for the conduct of the full

study including personnel, space, laboratory equipment and procedures and determined

that they are all feasible.

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rate. Completion of questionnaires and implementation of sample processing protocols

are feasible.

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Strengths:



• We established feasibility of study procedures including consenting, questionnaire

administration, sample collection, and laboratory procedures

Limitations:

• We approached 210 potential participants, and of the 112 (53%) who agreed to

participate, 30 (26.8%) completed the study visit over 7 months. which is lower

than the predicted rate of 50%



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Introduction



mortality, and considerable morbidity, including obesity and diabetes, in survivors.1-6

The


(SCBT) include hypothalamic damage,7-9

deficiency of pituitary hormones,7 8 10

reduced

mobility and physical activity levels,11-14

reduced exercise capacity and motivation,15 16

sleep

disturbances,17

visual compromise, imbalance and pain,18 19


steroids, antidepressants).20

Defining the mechanisms of obesity and diabetes in survivors


quality of life.



microenvironment that regulates tumor cell growth, metastasis and metabolism.21 22

One of


neighboring areas and differentiates to tumor-associated macrophages.21

While these cells


in survivors is unknown.23 24

Obesity is characterized by both local and systemic inflammatory responses.25 26


inflammation,27-31

and these cytokines can enter the circulation causing systemic

inflammation.32-35

In turn, inflammation causes insulin resistance and, if the latter is

untreated, will lead to type 2 diabetes.31


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inflammatory marker C-Reactive Protein (CRP);36

CRP this is not a satisfactory marker of

inflammation in children.37 38

In the general pediatric population with no history of cancer,

our group39

and others have reported some of the cytokines associated with childhood

obesity.40-45




ChIlDrEn (CanDECIDE study) was initiated. The protocol for the study has already been

published,46

and the aim of this pilot study was to evaluate study processes and procedures

to determine feasibility of the full study.

The primary aim of this pilot study was to test the feasibility of the CanDECIDE study

including recruitment rates, data collection forms’ content and design, data completion, time

needed to interview participants, feasibility of fasting and biological sample collection. In

addition, we wanted to test laboratory procedures to process samples including time, space,

equipment, personnel, consumables and additional resources needed.

Methods


tertiary pediatric center in Hamilton, Ontario, Canada; the Hamilton Integrated


clinics at the Hospital, and description of the setting has been published previously.46

The



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Inclusion criteria. We included boys and girls, aged 5 years and older, who were lean (BMI

below 85th



age and gender), and for SCBT we included those who had completed tumor therapy at least

6 months earlier.

Exclusion criteria. We excluded children on steroids or immunosuppressant therapy,


Data collection & instruments. We used standardized tools to collect data comprising

diet,47 48

physical activity,49

sleep,50

stress,51

and neighborhood walkability.52

Additional data collected include age, sex, ethnicity, education, profession, social history,

medical history, medications, illicit drug use, alcohol consumption, smoking, birth history,

menstrual history in girls, and family history. We designed a Case Report Form specifically

for the study, and collected data including diagnosis, location of tumor, treatment(s),

comorbidities, height, weight, waist circumference, hip circumference, BMI, blood pressure,

heart rate, and grip strength.46

Adiposity was measured using bioelectrical impedance with

Tanita scale (Tanita Corporation)53

for those less than 18 years of age, and the InBody520

body composition analyzer (GE Healthcare) for those 18 years or older.54

Sample collection & laboratory processing. All blood and urine samples were collected in

the fasting state. Fasting was started from midnight for at least 8 hours. Due to the age group

the study is dealing with, children were allowed to drink water but sugary drinks and food

were not allowed until sample collection was completed. Experienced pediatric

phlebotomists and/or researchers collected blood samples, and samples were processed

within 2 hours of collection. For saliva, participants either gave fasting samples, or had

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breakfast and then waited for at least 30 minutes before providing the samples using

Oragene saliva collection kits (DNA genotek, Ontario, Canada) as recommended by the

manufacturer.

Feasibility of study procedures. The primary outcome for this study was to evaluate the









5- The feasibility of analytes’ isolation and processing in the laboratory including

monocytes, serum, plasma, buffy coat, urine, and saliva.

Feasibility criteria. In this feasibility study, we designed a priori criteria for a feasible study

which included the following conditions: recruitment rate of at least 50%, the consenting of

80% of participants to provide biological samples, 90% completion rate of all

questionnaires, and the ability to isolate monocytes, serum, plasma, buffy coat, urine and

saliva from at least 80% of samples. We also evaluated the resources needed to perform the

study, including personnel, space and laboratory utilization for sample processing.

Statistical analysis



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McMaster University.55

The analysis of feasibility outcomes was descriptive in nature, with



Results

Participant recruitment rate. Over the period from November 2012-July 2013, 210

potential participants agreed to be approached by the research team after their care provider

asked for permission; in the case of participants from the community, they contacted the

study team directly having heard about the study. Of those subjects, 112 (53%) agreed to

participate including 1 from the community, 23 from neurooncology, 11 from cardiology,

and 77 from orthopedic clinics. There were no major differences in recruitment rates

between neurooncology and other clinics. Subjects who did not wish to participate in the

study (n=98) cited different reasons for their decision including travel distance and

transportation (n=26), discomfort with blood sampling (n=24), no interest in research

participation (n=32), unavailability to attend research clinic visits due to scheduling conflicts

(n=13), and other reasons (n=3). For this pilot study, we completed the recruitment of 30

subjects within the above period, resulting in a recruitment rate of 26.8% (Figure 1).

Participant Demographics. As shown in Table 1, of the 30 subjects recruited 12 (n=4

female) were in the SCBT group and 18 (n=12 female) in the control group. The majority of

participants in both groups (83%) were Caucasian Europeans. In the SCBT group, the

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average age was 14.3±4.6 years, and 33% of SCBT were overweight/obese. One third had

received radiotherapy, 31% chemotherapy, 83% had surgery and the majority received

short-term steroids in perioperative period. The tumor types included 5 astrocytomas, 5

medulloblastomas, and 2 other types. The mean (SD) age in the non-cancer comparison

group was 12.6 (2.7) years, of whom 39% were overweight/obese.





samples. We did offer all participants the use of topical anesthetic patches for phlebotomy,

and only a few opted to use them. Once collected, the samples were then taken to the

research laboratory for further processing. In one patient, it was not possible to get blood

samples, giving a sample collection rate of 97%. The equipment utilization in the laboratory

was appropriate for the workload of this study, and 4 research students were trained in the

laboratory study procedures and were responsible for sample processing, aliquoting, storage

and cataloguing.

Biological sample isolation and processing in the laboratory. The following samples

were processed:


containing 150µl of 100mM EDTA. The samples were layered on Polymorphprep™

separation gradient (Cedarlane Labs, Oakville, Canada), and samples centrifuged at 650g for

35 minutes at room temperature with brakes off. To isolate monocytes, we removed the

mononuclear cell layer from the gradient and used EasySep™

magnetic bead Human

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Monocyte Enrichment Kit without CD16 depletion (Stemcell Technologies, Vancouver,

Canada) as per manufacturer’s instructions.





until further use.



further use.

Urine: Fasting urine samples were collected in 90 ml urine containers, then aliquoted and

frozen at -80 °C.

Saliva: Saliva samples were stored at room temperature until further use.

Feasibility results. In this study, we approached potential participants over a 7-month

period. The number of those who agreed to participate was 112 (53%). So far, we have

completed the study on 30 subjects giving a recruitment rate of 26.8%, which is lower that

our target of 50%.







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need to cover clinics during the week for recruitment and staffing of the research clinic

visits. These students were provided with specific training to approach potential participants,














Discussion





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additional study procedures including consenting, data collection, entry, and analysis. We

also demonstrate the feasibility of sample collection and laboratory sample processing

protocols and techniques.

Study strengths. One of the significant strengths of this study was the establishment of

collaborations among several clinical teams within the Hospital to recruit study participants.

The alliance created by this collaboration demonstrates the feasibility of the expansion of

this platform to conduct the full study. As we serve 2.3 million people in our catchment

area, this represents close to 8% of the whole population of Canada, which is a

representative population of children.



data and demonstrated the feasibility of this structure for use in the full study with no

modifications.

Lessons learned to inform the design of CanDECIDE study. One of the limitations we

faced during this pilot phase was related to recruitment targets. We envisaged initially

recruiting 300 participants over 2 years; this was based on 50% projected recruitment rate,

and seeing around 3 patients per week. The recruitment rate for the feasibility study was

26.8%, as scheduling these patients to clinic visits was taking longer than we had anticipated

at first. This was because sometimes the team could not use the phone number or e-mail

address provided to contact the family, or scheduling conflicts for families prevented them

from attending study visits and they needed to reschedule. To address this, our next step is to

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prolong the recruitment phase to 4 years to try to address this issue. In addition, we had to

broaden the inclusion of other types of brain tumors, as we were focusing only on

astrocytomas, medulloblastomas and ependymomas. The caveat to this is increased

heterogeneity of the samples, which may then require a larger sample size to achieve

sufficient power to detect meaningful differences in inflammatory marker levels. One

possible avenue that may shorten the recruitment duration and maintain homogeneity of the

sample is collaboration with other centers caring for SCBT. We have already started


may help circumvent the issue of recruitment rates. As we forge collaborations with other

neurooncology centers, our sample will certainly be more representative of pediatric

populations in industrialized countries.

Ultimately, the challenge is to get the neurooncology patients to participate in the study, and

then to match the comparison group to those who participate. At this point, the groups are

different, and this is a reflection of the early stage of the study. We will ensure that the

groups are more homogeneous moving forward by periodically balancing the two groups

through ensuring that the comparison group is age and sex matched to the survivors group.

Another approach that we will adopt is to broaden community access by advertising in

schools and recreational facilities. We will also add incentives including paying for costs of

parking and providing small tokens for participation.




same clinic, which allows us to maintain relatively high rates of longitudinal follow-up.

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to minimize selection bias is to ensure that recruited participants are free from disease or

have a self-limiting condition. For example, participants recruited from the orthopedic clinic

are seen in research study visits after their fractures are healed; our recruits from the

cardiology clinic were assessed for cardiac defects and only included if they had a





e.g. family history details of grandparents. For SCBT, all clinical data regarding care have


form of bias.





Conclusions

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study procedures are accomplishable. However, we will need to prolong the recruitment




changes suggested.

Acknowledgements

We would like to acknowledge the study participants and their families for contributing

to the study. We also would like to acknowledge the McMaster University students who

helped with study visit conduct and laboratory procedures: Ms. Amrita Amarnaney, Ms.

Pauline Chang, Ms. Connie Cheung, Ms. Jiyeh Joo, Mr. Ishan Aditya, Mr. Nicola Sahar,

Mr. Ameir Makar, Mr. Calvin Tang, Ms. Glara Rhee, Ms. Brittany Watson, and Ms.

Madeleine Bondy.

Contributorship statement: MCS conceived the study question and generated the

hypotheses. MCS, LT, RD, RDB, SB and KS finalized the study design. MCS, KWW,

MV and LT completed the statistical analysis plans. MCS, RD, SB, RDB and KS

contributed to the definition of study cohorts, inclusion and exclusion criteria,

recruitment plan and study logistics including space and resource allocation.

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Competing interests: None declared by the authors

Funding: This study was partly funded by Joshua’s Journey (Hamilton Health Sciences



Data sharing: The additional data include additional clinical data based on the

questionnaires reported in our protocol paper including diet, physical activity, sleep,

stress, and build environment. This paper is focused on reporting feasibility, and the data

will be included in the full study for analyses and publications. As the data collection is

ongoing, and data are not fully analyzed, the data will be available at the end of the study

to collaborators in an agreed upon format at that point in time.

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References:












Oncol 2012;30(16):2005-12.


F. 2011.


2010;36(4):277-85.


2003;15(1):3-9.






2003;88(6):2586-92.

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2009;27(14):2396-404.











2008;31(2):271.


















2012;4:325-34.



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Biol 2011;90(12):1000-15.







Invest 2003;112(12):1796-808.




2009;29(7):988-96.














Metab 2003;284(4):E741-47.









Metab 2009;22(2):153-9.




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21










82.



2009;32(6):e71.



Metab 2009;22(10):905-14.



Biomed 2009;80(2):117-23.







1997;26(6):808-16.

48.



9th-2013).



202.











health 2004;94(3):473-83.

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Variable

Control

(n=18)

SCBT

(n=12)

Mean SD Mean SD

Age (years) 12.6 2.7 14.3 4.6

Height (cm) 156.7 11.6 151.5 23.6

Weight (kg) 54.0 15.0 52.5 24.0

BMI (kg/m2) 21.7 4.6 21.8 6.7


% Fat mass 24.1 8.6 23.3 13.0



Heart rate (bpm) 78.9 9.5 85.5 10.6

Systolic BP (mmHg) 107.9 9.5 99.3 11.6


Birth weight (g) 3,550 598 3,611 657




BMI=Body mass index

BP=Blood pressure

Table 1

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1

Recruitment feasibility to a cohort study of ascertain endocrine and metabolic health

among survivors of childhood brain tumors: A report from the Canadian study of

Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE)




Dillenburg1,6, Ronald Barr1,3, Kuan-Wen Wang1,2, Marlie Valencia1,2, Lehana

Thabane1,7,8,9,10


: [email protected]


: [email protected]



: [email protected]

Ronald Barr1,3

: [email protected]

K.W. Wang1,2: [email protected]

Marlie Valencia1,2: [email protected]

Lehana Thabane1,7,8,9,10: [email protected]

1Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada 2Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario,





Canada 7Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton,

Ontario, Canada 8Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada 9Centre for Evaluation of Medicines, Hamilton, ON, Canada 10

Biostatistics unit, St Joseph’s Healthcare-Hamilton, Hamilton, Ontario, Canada


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Abstract:





tumors.



below 85th centile for age and gender) or overweight/obese (BMI 85th centile or above for



participation. We approached 210 potential participants, and 112 (53%) agreed to

participate. Of the latter group, 30 (26.8%) have already completed the study visit over 7

months.

Outcomes: Feasibility targets included were: recruitment rate of at least 50%, the

consenting of 80% of participants to provide biological samples, 90% completing all

questionnaire completion rates, and the ability to process biological samples fromor at

least 80% of participants.

Results: We approached 210 potential participants, and of the 112 (53%) who agreed to

participate, 30 (26.8%) completed the study visit over 7 months. Our recruitment rate was

26.8% (30/112), and Aall participants those who consented agreed to fast, provide

biological samples and complete the questionnaires. Sample collection was successful in

97% (29/30) of participants and laboratory procedures were feasible in 100% of

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collected samples. We also tested resources required for the conduct of the full study

including personnel, space, laboratory equipment and procedures and determined that

they are all feasible.




rate. Completion of questionnaires and implementation of sample processing protocols

are feasible.

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Strengths:



• We established feasibility of study procedures including We found that the study

is feasible, with consenting, questionnaire administration, sample collection, rates

of 97%, and laboratory procedures were achievable in all cases.

Limitations:

• We approached 210 potential participants, and of the 112 (53%) who agreed to

participate, 30 (26.8%) completed the study visit over 7 months.Our

recruitment rate was 26.8% (30/112), which is lower

• than the predicted rate

of 50%



Formatted: Indent: Left: 0.5", No bulletsor numbering

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Introduction:



mortality, and considerable morbidity, including obesity and diabetes, in survivors.1-6. The


(SCBT) include hypothalamic damage,7-9

, deficiency of pituitary hormones,7 8 10

, reduced

mobility and physical activity levels,11-14

, reduced exercise capacity and motivation,15 16

,

sleep disturbances,17

, visual compromise, imbalance and pain,18 19


steroids, antidepressants).20. Defining the mechanisms of obesity and diabetes in survivors


quality of life.



microenvironment that regulates tumor cell growth, metastasis and metabolism.21 22

. One of


neighboring areas and differentiates to tumor-associated macrophages.21. While these cells


in survivors is unknown.23 24

.

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Obesity is characterized by both local and systemic inflammatory responses.25 26

.


inflammation,27-31, and these cytokines can enter the circulation and causinge systemic

inflammation.32-35

. In turn, inflammation causes insulin resistance and, if the latter is

untreated, will lead to type 2 diabetes.31

.



inflammatory marker C-Reactive Protein (CRP);36; CRP but this is not a satisfactory marker

of inflammation in children.37 38. In the general pediatric population with no history of

cancer, our group39

and others have reported some of the cytokines associated with

childhood obesity.40-45




ChIlDrEn (CanDECIDE study) was initiated. T; the protocol for the study which has already

been published,.46

and tThe aim of this pilot study was to evaluate study processes and

procedures to determine the feasibility of the full study.

Objectives: The primary aim of this pilot study was to test the feasibility of the

CanDECIDE study including recruitment rates, data collection forms’ content and design,

data completion, time needed to interview participants, feasibility of fasting and biological

sample collection. In addition, we wanted to , and test ing of laboratory procedures to

process samples including time, space, equipment, personnel, consumables and additional

resources needed.

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Methods:


tertiary pediatric center in Hamilton, Ontario, Canada; t. The Hamilton Integrated


clinics at the Hospital, and description of the setting has been published previously.46 The




Inclusion criteria. : We included boys and girls, aged 5 years and older, who were lean

(BMI below 85th


centile or above

for age and gender), and for SCBT we included those who had completed tumor therapy at

least 6 months earlier.

Exclusion criteria. : We excluded children on steroids or immunosuppressant therapy,


Data collection & instruments. : We used standardized tools to collect data comprising

diet,47 48

, physical activity,49

, sleep,50

, stress,51

, and neighborhood walkability.52

.

Additional data collected include age, sex, ethnicity, education, profession, social history,

medical history, medications, illicit drug use, alcohol consumption, smoking, birth history,

menstrual history in girls, and family history. We designed a Case Report Form specifically

for the study, and collected data including diagnosis, location of tumor, treatment(s),

comorbidities, height, weight, waist circumference, hip circumference, BMI, blood pressure,

heart rate, and grip strength.46

. Adiposity was measured using bioelectrical impedance with

Tanita scale (Tanita Corporation)53 for those less than 18 years of age, and the InBody520

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body composition analyzer (GE Healthcare) for those 18 years or older.54

.

Sample collection &and laboratory processing. :

All blood and urine samples were collected in the fasting state. Fasting was started from

midnight for at least 8 hours. Due to the age group the study is dealing with, children were

allowed to drink water but sugary drinks and food were not allowed until sample collection

was completed. Experienced pediatric phlebotomists and/or researchers collected blood

samples, and samples were processed within 2 hours of collection. For saliva, participants

either gave fasting samples, or had breakfast and then waited for at least 30 minutes before

providing the samples using Oragene saliva collection kits (DNA genotek, Ontario, Canada)

as recommended by the manufacturer.

Feasibility of study procedures. : Tthe primary outcome for this study was to evaluate the









5- The feasibility of analytes’ isolation and processing in the laboratory , including

monocytes, serum, plasma, buffy coat, urine, and saliva.

Feasibility criteria. :

In this feasibility study, we designed a priori criteria for a feasible study which included the

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following conditions: a recruitment rate of at least 50%, the consenting of 80% of

participants to provide biological samples, 90% completion rate of all questionnaires, and

the ability to isolate monocytes, serum, plasma, buffy coat, urine and saliva from in at least

80% of samplesparticipants. We also evaluated the resources needed to perform the study,

including personnel, space and laboratory utilization for sample processing.

Statistical analysis:







McMaster University.55 The analysis of feasibility outcomes was descriptive in nature, with



Results:

Participant recruitment rate. :

Over the period from November 2012-July 2013, 210 potential participants agreed to be

approached by the research team after their care provider asked for permission; in the case

of participants from the community, they contacted the study team directly having heard

about the study. Of those subjects, 112 (53%) agreed to participate including 1 from the

community, 23 from neurooncology, 11 from cardiology, and 77 from orthopedic clinics.

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There were no major differences in recruitment rates between neurooncology and other

clinics. Subjects who did not wish to participate in the study (n=98) cited different reasons

for their decision including travel distance and transportation (n=26), discomfort with blood

sampling (n=24), no interest in research participation (n=32), unavailability to attend

research clinic visits due to scheduling conflicts (n=13), and other reasons (n=3). For this

pilot study, we completed the recruitment of 30 subjects within the above period, resulting

in a recruitment rate of 26.8% (Figure 1).

Participant Demographics. :

As shown in Table 1, of the 30 subjects recruited 12 (n=4 female) were in the SCBT group

and 18 (n=12 female) in the control group. The majority of participants in both groups

(83%) were Caucasian Europeans. In the SCBT group, the average age was 14.3±4.6 years,

and 33% of SCBT were overweight/obese. One third had received radiotherapy, 31%

chemotherapy, 83% had surgery and the majority received short-term steroids in

perioperative period. The tumor types included 5 astrocytomas, 5 medulloblastomas, and 2

other types. The mean (SD) age in the non-cancer comparison group was 12.6 (2.7) years, of

whom 39% were overweight/obese.





samples. We did offer all participants the use of topical anesthetic creams or patches for

phlebotomy, and only a few opted wanted to use them. Once collected, the samples were

Formatted: List Paragraph

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then taken to the research laboratory for further processing. In one patient, it was not

possible to get blood samples, giving a sample collection rate of 97%. The equipment

utilization in the laboratory was appropriate for the workload of this study, and 4 research

students were trained in the laboratory study procedures and were responsible for sample

processing, aliquoting, storage and cataloguing.

Biological sample isolation and processing in the laboratory. The following samples

were processed::


containing 150µl of 100mM EDTA. The samples were layered on Polymorphprep™

separation gradient (Cedarlane Labs, Oakville, Canada), and samples centrifuged at 650g for

35 minutes at room temperature with brakes off. To isolate monocytes, we removed the

mononuclear cell layer from the gradient and used EasySep™

™ magnetic bead Human

Monocyte Enrichment Kit without CD16 depletion (Stemcell Technologies, Vancouver,

Canada) as per manufacturer’s instructions., to isolate monocytes within 2 hours of sample

collection.





until further use.



further use.

Formatted: Font: (Default) Times NewRoman, Not Bold

Formatted: Font: (Default) Times NewRoman, Not Bold

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Urine: Fasting urine samples were collected in 90 ml urine containers, then and aliquoted

and frozen at -80 °C.

Saliva: Saliva samples were collected either while the participants were fasting or at least 30

minutes after food or drink. Samples were collected using Oragene-DNA collection kits

(DNA Genotec Inc., Ontario, Canada), and stored at room temperature until further use.

Feasibility results. :

In this study, we approached potential participants over a 7-month period. The number of

those who agreed to participate was 11297 (531%). So far, we have completed the study on

30 subjects giving a recruitment rate of 26.831%, which is . This is lower that our target of

50% recruitment rate.










need to cover clinics during the week for recruitment and staffing of the research clinic

visits. These students were provided with specific training to approach potential participants,



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Discussion:







additional study procedures including consenting, data collection, data entry, and data

analysis. We also demonstrate the feasibility of , sample collection and and laboratory

sample processing protocols and techniques.

Study strengths:.

One of the significant strengths of this study was the establishment of collaborations among

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several clinical teams within the Hospital to recruit study participants. The alliance created

by this collaboration demonstrates the feasibility of the expansion of this platform to

conduct the full study. As we serve 2.3 million people in our catchment area, this represents

close to 8% of the whole population of Canada, which is a representative population of

children.



data and demonstrated the feasibility of this structure for use in in the full study with no

modifications.

Lessons learned to inform the design of CanDECIDE study:.

One of the limitations we faced during this pilot phase was related to recruitment targets.

We envisaged initially recruiting 300 participants over 2 years; this was based on 50%

projected recruitment rate, and seeing around 3 patients per week. The recruitment rate for

the feasibility study was 26.8%, as scheduling these patients to clinic visits was taking

longer than we had anticipated at first. This was because sometimes the team could not use

the phone number or e-mail address provided to contact the family, or scheduling conflicts

for families prevented them from attending study visits and they needed to reschedule. To

address this, our next step is to prolong the recruitment phase to 4 years to try to address this

issue. In addition, we had to broaden the inclusion of other types of brain tumors, as we

were focusing only on astrocytomas, medulloblastomas and ependymomas. The caveat to

this is increased heterogeneity of the samples, which may then require a larger sample size

to achieve sufficient power to detect meaningful differences in inflammatory marker levels.

One possible avenue that may shorten the recruitment duration and maintain homogeneity of

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the sample is collaboration with other centers caring for SCBT. We have already started


may help circumvent the issue of recruitment rates. As we forge collaborations with other

neurooncology centers, our sample will certainly be more representative of pediatric

populations in industrialized countries.

Ultimately, the challenge is to get the neurooncology patients to participate in the study, and

then to match the comparison group to those who participate. At this point, the groups are

different, and this is a reflection of the early stage of the study. We will ensure that the

groups are more homogeneous moving forward by periodically balancing the two groups

through ensuring that the comparison group is age and sex matched to the survivors group.

Another approach that we will adopt is to broaden community access by advertising in

schools and recreational facilities. We will also add incentives including paying for costs of

parking and providing small tokens for participation.




same clinic, which allows us to maintain relatively high rates of longitudinal follow-up.







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to minimize selection bias is to ensure that recruited participants are free from disease and or

have a self-limiting or stable condition. For example, participants recruited from the

orthopedic clinic are seen in research study visits after their fractures are healed; our recruits

from the cardiology clinic were assessed for cardiac defects and only included if they had a





e.g. family history details of grandparents. For SACBT, all clinical data regarding care have


form of bias.





Conclusions:


study procedures are accomplishable. However, we will need to prolong the recruitment




changes suggested.

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Acknowledgements:

We would like to acknowledge the study participants and their families for

participatingcontributing toin the study. We also would like to acknowledge the

McMaster University students who helped with study visit conduct and laboratory

procedures: Ms. Amrita Amarnaney, Ms. Pauline Chang, Ms. Connie Cheung, Ms. Jiyeh

Joo, Mr. Ishan Aditya, Mr. Nicola Sahar, Mr. Ameir Makar, Mr. Calvin Tang, Ms. Glara

Rhee, Ms. Brittany Watson, and Ms. Madeleine Bondy.

This study was partly funded by Joshua’s Journey (Hamilton Health Sciences

Foundation) Neurooncology fund. MCS is funded by New Investigator Fund grant

from Hamilton Health Sciences.

Contributorship statement: MCS conceived the study question and generated the

hypotheses. MCS, LT, RD, RDB, SB and KS finalized the study design. MCS, KWW,

MV and LT completed the statistical analysis plans. MCS, RD, SB, RDB and KS

contributed to the definition of study cohorts, inclusion and exclusion criteria,

recruitment plan and study logistics including space and resource allocation.




Competing interests: None declared by the authors

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Funding: This study was partly funded by Joshua’s Journey (Hamilton Health Sciences



Data sharing: The additional data include additional clinical data based on the

questionnaires reported in our protocol paper including diet, physical activity, sleep,

stress, and build environment. This paper is focused on reporting feasibility, and the data

will be included in the full study for analyses and publications. As the data collection is

ongoing, and data are not fully analyzed, the data will be available at the end of the study

to collaborators in an agreed upon format at that point in time.



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References:












Oncol 2012;30(16):2005-12.


F. 2011.


2010;36(4):277-85.


2003;15(1):3-9.






2003;88(6):2586-92.









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2009;27(14):2396-404.











2008;31(2):271.


















2012;4:325-34.









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Biol 2011;90(12):1000-15.







Invest 2003;112(12):1796-808.




2009;29(7):988-96.














Metab 2003;284(4):E741-47.









Metab 2009;22(2):153-9.










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82.



2009;32(6):e71.



Metab 2009;22(10):905-14.



Biomed 2009;80(2):117-23.







1997;26(6):808-16.

48.



9th-2013).



202.











health 2004;94(3):473-83.









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Figure 1

Variable

Control

(n=18)

SCBT

(n=12)

Mean SD Mean SD

Age (years) 12.6 2.7 14.3 4.6

Height (cm) 156.7 11.6 151.5 23.6

Weight (kg) 54.0 15.0 52.5 24.0

BMI (kg/m2) 21.7 4.6 21.8 6.7


Par cipants approached for recruitment in

clinics or in community

(n=210)

Subjects mee ng the eligibility criteria for

par cipa on in the study

(n=210)

Subjects agreeing to par cipate in the

study

(n=112)

Subjects refusing to par cipate in

the study

(n=98)

Subjects who completed recruitment so

far

(n=30)

Reasons for refusal

- Transporta on/distance (n=26)

- Blood sampling concerns (n=24)

- No interest in par cipa on (n=32)

- Schedule conflicts (n=13)

- Other (n=3)


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% Fat mass 24.1 8.6 23.3 13.0



Heart rate (bpm) 78.9 9.5 85.5 10.6

Systolic BP (mmHg) 107.9 9.5 99.3 11.6


Birth weight (g) 3,550 598 3,611 657




BMI=Body mass index

BP=Blood pressure

Table 1

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Figure 1

254x190mm (72 x 72 DPI)

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