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| Name | Class |
|---|---|
| Canadian Institutes of Health Research (CIHR) | OTHER_GOV |
| Canadian Cancer Society (CCS) | OTHER |
| C17 Council | OTHER |
| Garron Family Cancer Centre |
To find possible therapeutic targets to help prevent long-term brain and behavioural side effects in survivors of childhood leukemia that may have been caused by chemotherapy (Treatment-Related late Adverse Neuro-Cognitive Effects: TRANCE). The study hypothesis is that genetic variations of the elements in the folate-related cycles and methotrexate disposition networks are associated with the deficit phenotype (TRANCE) of childhood leukemia survivors.
Hypothesis Genetic variants of the elements in the folate-related cycles and methotrexate disposition networks are associated with the TRANCE phenotype of childhood leukemia survivors.
Objectives
Study design: A case-control study of leukemia survivors
Analyses
Leukemia survivors will be characterized by their status of neurocognitive function, and categorized into the Deficit case and the non-deficit Control case.
They will be also characterized by the following attributes
Comparative analyses between neuro-cognitiive deficit phenotype (TRANCE) and Control on those parameters
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Leukemia survivors with neurocognitive deficit | Leukemia survivors with neuro-cognitive deficit phenotype. Based on DIVERGET and other phenotyping tools, we will identify those with the deficit phenotype. This will be treated as "case". | ||
| Leukemia survivors without neurocognitive deficit | Leukemia survivors who did not show impaired neurocognitive function, compared to the Control group defined above. |
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| Measure | Description | Time Frame |
|---|---|---|
| DIVERGET | This is a short battery of tests that has been shown to be predictive of both global and academic impairment in survivors of childhood cancer. All neuro-cognitive tests are done on a same day. | Within 6 months from the enrolment |
| Stop Signal Task (SST) | Response inhibition, disturbed by behavioral inattention, will be characterized using our task-based computer program, the Stop Signal Task (SST). All neuro-cognitive tests are done on a same day. | Within 6 months from the enrolment |
| CONNERS 3 | To characterize behavioural aspects, we will administer the standard measure based on parent report. All neuro-cognitive tests are done on a same day. | Within 6 months from the enrolment |
| Pathway-based gene variant status | In the hypothesis-driven genome-wide approach, we will focus on the candidate pathways/regions including (but not limited to): a) Folate/methionine cycle genes and transporters; b) drug metabolizing enzymes and transporters (including families of CYP, SLC and ABC transporters); c) epigenetic modifying factors; and d) neuro-regeneration and tissue repair. | Within 3 months from the end of enrolment |
| Measure | Description | Time Frame |
|---|---|---|
| WISC-IV | In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will include tests of general cognitive function (WISC-IV). All neuro-cognitive tests are done on a same day. | Within 6 months from the enrolment |
| WIAT-III numerical operations and math fluency composite score |
| Measure | Description | Time Frame |
|---|---|---|
| Epigenetics marker | DNA methylation signals represent one of the most stable epigenetic markers, which are known to be affected by environmental factors including drugs and nutrients such as folate. Environmental information conveyed through these factors is translated into gene expression changes mediated by DNA methylation. Although this may contribute to neuro-cognitive deficits of the leukemia survivors, there is no prior data in this regard. Therefore, the aim of this exploratory analysis is to determine if there is any indication that DNA methylation patterns are altered in the participants. DNA will be isolated from each of the blood, buccal swab, and saliva samples and modified using sodium bisulfite, which will then be used to determine DNA methylation patterns. |
Inclusion Criteria:
Exclusion Criteria:
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Childhood leukemia survivors
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| Name | Affiliation | Role |
|---|---|---|
| Dr. Shinya Ito, MD | The Hospital for Sick Children | Principal Investigator |
| Dr. Sharon Guger | The Hospital for Sick Children | Principal Investigator |
| Dr. Johann Hitzler | The Hospital for Sick Children | Principal Investigator |
| Dr. Deborah L O'Connor | The Hospital for Sick Children | Principal Investigator |
| Dr. Russell Schachar | The Hospital for Sick Children | Principal Investigator |
| Dr. Brenda Spiegler | The Hospital for Sick Children | Principal Investigator |
| Dr. Rosanna Weksberg | The Hospital for Sick Children | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Hospital for Sick Children | Toronto | Ontario | M5G 1X8 | Canada |
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| ID | Term |
|---|---|
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| D007938 | Leukemia |
| D020258 | Neurotoxicity Syndromes |
| ID | Term |
|---|---|
| D007945 | Leukemia, Lymphoid |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
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| OTHER |
| Pediatric Oncology Group of Ontario | OTHER |
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DNA samples obtained via blood, saliva and buccal sample collection.
In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will include tests of general cognitive function: WIAT-III numerical operations and math fluency composite score. All neuro-cognitive tests are done on a same day. |
| Within 6 months from the enrolment |
| Brief Rating Inventory of Executive Function (BRIEF) | In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will administer Brief Rating Inventory of Executive Function (BRIEF), which is designed to assess executive functioning in the home environment. All neuro-cognitive tests are done on a same day. | Within 6 months from the enrolment |
| N-Back Task | In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will administer N-Back Task, which is a continuous performance computerized task used to measure aspects of working memory. All neuro-cognitive tests are done on a same day. | Within 6 months from the enrolment |
| Folate, vitamin B12 and iron intake | Folate and other vitamin intakes vary among individuals. Folic acid fortification in Canadian food product has changed the Canadian population norm of folate status, virtually eliminating folate deficiency status. However, a large inter-individual variation still remains. We will use a Supplement Questionnaire to capture information on all and any supplements that participants may be currently taking. | Within 6 months from the enrolment |
| Folate status | In order to complement the Supplement Questionnaire (above), we will measure the folate concentration in plasma and red blood cells. | Within 6 months from the enrolment |
| Serum vitamin B12 | Vitamin B12 and folate pathways interact to maintain biochemical homeostasis. To complement the intake assessment (above), we will measure serum vitamin B12. | Within 6 months from the enrolment |
| Iron status | Iron status affects cognitive function of children. In addition to the intake assessment (above), we will estimate iron status by measuring hemoglobin and soluble transferrin receptor. | Within 6 months from the enrolment |
| Within 3 months from the end of enrolment |
| D006425 |
| Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D009422 | Nervous System Diseases |
| D011041 | Poisoning |
| D064419 | Chemically-Induced Disorders |