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| Name | Class |
|---|---|
| Children's National Research Institute | OTHER |
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The purpose of this study is to use various types of MRI and cognitive testing to evaluate changes in the brain and cognitive function that occur in subjects with ornithine transcarbamylase deficiency (OTCD) relative to healthy individuals
The overall goal of this project is to characterize metabolic, structural and cognitive changes in OTCD using 1H MRS, DTI, volumetric averaging and fMRI with cognitive testing of executive function measures to validate biomarkers for the effect of HA and its treatment on the brain.
The investigators will measure gln and mI in blood and brain (using 1H MRS) in affected participants, and mI in brain in controls, fractional anisotropy as a measure of white matter microstructural damage (by DTI) and brain activation pathways alterations with tasks probing working memory (fMRI). As a secondary outcome measure, the investigators will correlate the findings from neuroimaging with cognitive functioning. This protocol is based on the previous 5104 protocol, now includes children to evaluate the age and stage of disease on these indices in a cohort that is undergoing important developmental events against an age matched typically developing cohort.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Subjects with OTCD | males and females ages 7-60 years with OTCD who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing |
| |
| Healthy controls | males and females ages 7-60 years who are healthy controls who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MRI scanning | Other | 1H MRS, DTI, FMRI |
|
| Measure | Description | Time Frame |
|---|---|---|
| Concentration of Glutamine and Myoinositol | Concentration based on area under curve on 1H Magnetic Resonance Spectroscopy(MRS) and quantitated by LCModel (a method that allows automatic quantitation of spectroscopy data). A metabolite's tissue concentration is related to the integrated amplitude, the area under the curve of the MRS signal, it produces. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point. Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM). | Baseline |
| Functional Connectivity of Assessed by Resting-state fMRI | Investigation of differences in functional connectivity of OTCD patients compared to healthy controls, particularly in the default-mode network (DMN) and the set-maintenance network (SMN). Participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, identified the nodes that comprised each network in each group, and assessed internodal connectivity. For each subject, this analysis generated a correlation value, which reflected the strength of functional connectivity between each ROI pair.The correlation r-values were normalized using Fisher's r-to-Z-transform, generating z-scores. The DMN was composed of 1) anterior cingulate/medial prefrontal cortex (ACC/mPFC), 2) posterior cingulate cortex (PCC), and 3) bilateral inferior parietal lobule (IPL). The SMN was composed of 1)ACC, 2) bilateral superior frontal gyrus (SFG), and 3) bilateral anterior insula/frontal operculum (aI/fO). | Baseline |
| Fractional Anisotropy Assessed Using DTI | Fractional Anisotropy (FA) is a measure of the diffusion asymmetry within a voxel as defined by its eigenvalues. In our study, FA is being used as a measure of white matter integrity, because FA is very sensitive to small microstructural changes.Fractional anisotropy (FA) is a scalar value between zero and one (0-1) that describe anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions. |
| Measure | Description | Time Frame |
|---|---|---|
| Neuropsychological Assessment | Testing consisted of the Wechsler Abbreviated Scale of Intelligence (WASI), Comprehensive Trail Making Test (CTMT) (range 17-87), and the Behavioral Rating Inventory of Executive Function (BRIEF) (range GEC: 70-210; BRI:39-82 ; MI:41-92). The WASI includes three measures of intelligence; including, performance IQ (sum of block design and matrices sub scales; range: 40-160), verbal IQ (sum of vocabulary and similarities sub scales; range 40-160), and total IQ (sum of all four subscales; range: 80-320). The CTMT measures simple attention and executive function, it consists of five dot to dots that increase with complexity and difficulty. Higher values indicate better outcomes for all scales. |
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Inclusion Criteria:
Subject inclusion criteria:
Control participant inclusion criteria:
Exclusion Criteria:
Subject exclusion criteria:
Control exclusion criteria:
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Males and females, ages 7-60 years with ornithine transcarbamylase deficiency Males and females, ages 7-60 years who are healthy controls without ornithine transcarbamylase deficiency
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| Name | Affiliation | Role |
|---|---|---|
| Andrea L Gropman, M.D. | Children's National Research Institute | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22110002 | Background | Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, VanMeter J. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum Brain Mapp. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23. | |
| 21778100 | Background |
| Label | URL |
|---|---|
| Family support group | View source |
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Final data is on the UCDC website
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| ID | Title | Description |
|---|---|---|
| FG000 | Subjects With OTCD | males and females ages 7-60 years with OTCD MRI scanning: 1H Magnetic Resonance Spectroscopy (MRS), Diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI) Cognitive testing: Neuropsychological testing |
| FG001 | Healthy Controls | males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Subjects With OTCD | males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing |
| BG001 | Healthy Controls | males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Concentration of Glutamine and Myoinositol | Concentration based on area under curve on 1H Magnetic Resonance Spectroscopy(MRS) and quantitated by LCModel (a method that allows automatic quantitation of spectroscopy data). A metabolite's tissue concentration is related to the integrated amplitude, the area under the curve of the MRS signal, it produces. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point. Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM). | Two OTCD patients and one healthy control were excluded due to excessive head motion. | Posted | Mean | Standard Deviation | mM | Baseline |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Subjects With OTCD | males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Andrea Gropman | Children's National Medical Center | 202-476-2120 | agropman@childrensnational.org |
| ID | Term |
|---|---|
| D020163 | Ornithine Carbamoyltransferase Deficiency Disease |
| D022124 | Hyperammonemia |
| ID | Term |
|---|---|
| D056806 | Urea Cycle Disorders, Inborn |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
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| ID | Term |
|---|---|
| D009483 | Neuropsychological Tests |
| ID | Term |
|---|---|
| D011581 | Psychological Tests |
| D004191 | Behavioral Disciplines and Activities |
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| Cognitive testing | Behavioral | Behavioral testing |
|
| Baseline |
| Baseline |
| Prust MJ, Gropman AL, Hauser N. New frontiers in neuroimaging applications to inborn errors of metabolism. Mol Genet Metab. 2011 Nov;104(3):195-205. doi: 10.1016/j.ymgme.2011.06.020. Epub 2011 Jun 30. |
| 20488904 | Background | Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20. |
| 20207564 | Background | Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13. |
| 20004862 | Background | Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010 Jan;42(1):49-52. doi: 10.1016/j.pediatrneurol.2009.07.017. |
| 19567648 | Background | Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Radiology. 2009 Sep;252(3):833-41. doi: 10.1148/radiol.2523081878. Epub 2009 Jun 30. |
| 18662894 | Background | Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26. |
| Urea Cycle rare disease consortium | View source |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Subjects With OTCD | males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing |
| OG001 | Healthy Controls | males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing |
|
|
|
| Primary | Functional Connectivity of Assessed by Resting-state fMRI | Investigation of differences in functional connectivity of OTCD patients compared to healthy controls, particularly in the default-mode network (DMN) and the set-maintenance network (SMN). Participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, identified the nodes that comprised each network in each group, and assessed internodal connectivity. For each subject, this analysis generated a correlation value, which reflected the strength of functional connectivity between each ROI pair.The correlation r-values were normalized using Fisher's r-to-Z-transform, generating z-scores. The DMN was composed of 1) anterior cingulate/medial prefrontal cortex (ACC/mPFC), 2) posterior cingulate cortex (PCC), and 3) bilateral inferior parietal lobule (IPL). The SMN was composed of 1)ACC, 2) bilateral superior frontal gyrus (SFG), and 3) bilateral anterior insula/frontal operculum (aI/fO). | Resting state data was not acquired for several of our participants (7 controls and 4 patients). Furthermore, 3 OTCD patients were excluded from the analyses due to excessive head motion. | Posted | Mean | Standard Deviation | z-scores | Baseline |
|
|
|
|
| Primary | Fractional Anisotropy Assessed Using DTI | Fractional Anisotropy (FA) is a measure of the diffusion asymmetry within a voxel as defined by its eigenvalues. In our study, FA is being used as a measure of white matter integrity, because FA is very sensitive to small microstructural changes.Fractional anisotropy (FA) is a scalar value between zero and one (0-1) that describe anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions. | Posted | Mean | Standard Deviation | units on a scale | Baseline |
|
|
|
| Secondary | Neuropsychological Assessment | Testing consisted of the Wechsler Abbreviated Scale of Intelligence (WASI), Comprehensive Trail Making Test (CTMT) (range 17-87), and the Behavioral Rating Inventory of Executive Function (BRIEF) (range GEC: 70-210; BRI:39-82 ; MI:41-92). The WASI includes three measures of intelligence; including, performance IQ (sum of block design and matrices sub scales; range: 40-160), verbal IQ (sum of vocabulary and similarities sub scales; range 40-160), and total IQ (sum of all four subscales; range: 80-320). The CTMT measures simple attention and executive function, it consists of five dot to dots that increase with complexity and difficulty. Higher values indicate better outcomes for all scales. | Posted | Mean | Standard Deviation | units on a scale | Baseline |
|
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| EG001 | Healthy Controls | males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing | 0 | 29 | 0 | 29 |
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| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000592 | Amino Acid Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| DMN: ACC/mPFC & right IPL connectivity |
|
| DMN: PCC & left IPL connectivity |
|
| DMN: PCC & right IPL connectivity |
|
| DMN: left IPL & right IPL connectivity |
|
| SMN: ACC & left aI/fO connectivity |
|
| SMN: ACC & left SFG connectivity |
|
| SMN: ACC & right aI/fO connectivity |
|
| SMN: ACC & right SFG connectivity |
|
| SMN: left aI/fO & left SFG connectivity |
|
| SMN: left aI/fO & right aI/fO connectivity |
|
| SMN: left aI/fO & right SFG connectivity |
|
| SMN: left SFG & right SFG connectivity |
|
| SMN: right aI/fO & left SFG connectivity |
|
| SMN: right aI/fO & right SFG connectivity |
|
| The null hypothesis predicts that functional connectivity between the ACC/mPFC node and the left IPL node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.024 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the ACC/mPFC node and the PCC node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.040 | This is an uncorrected p-value. A priori significance threshold is 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the ACC/mPFC node and the right IPL node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.008 | This is an uncorrected p-value. A priori significance threshold was 0.05 | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the left IPL node and the right IPL node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.470 | This is an uncorrected p-value. A priori significance threshold was 0.05 | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the PCC node and the left IPL node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.829 | This is an uncorrected p-value. A priori significance threshold was 0.05 | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the PCC node and the right IPL node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.801 | This is an uncorrected p-value. A priori significance threshold was 0.05 | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis states predicts no main effects of Group, ROI pair, or Age, suggesting that the connectivity between all SMN nodes is the same across groups. | ANOVA | We ran a 2 (Group) x 6 (ROI Pair) ANOVA to assess functional connectivity between the nodes of the SMN, using age as a covariate. | <0.001 | Our a priori threshold for statistical significance was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the ACC node and the left aI/fO node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.550 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the ACC node and the left SFG node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.113 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the ACC node and the right aI/fO node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.039 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the ACC node and the right SFG node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.005 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the left aI/fO and the left SFG node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.426 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the left aI/fO node and the right aI/fO node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.256 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the left aI/fO and the right SFG node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.853 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the right aI/fO node and the left SFG node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.003 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| The null hypothesis predicts that functional connectivity between the right aI/fO node and the right SFG node does not differ between groups. | ANOVA | We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate. | 0.023 | This is an uncorrected p-value. A priori significance threshold was 0.05. | 2-Sided | Superiority or Other (legacy) |
| WASI - Full IQ |
|
| Trails - Composite |
|
| Brief - Behavioral Regulation Index (BRI) |
|
| Brief - Metacognition Index (MI) |
|
| Brief - Global Executive Composite Score (GEC) |
|
| .002 |
Equal variance not assumed. Comparison WASI performance IQ cases and controls |
| 2-Sided |
| Superiority or Other (legacy) |
| t-test, 2 sided | .094 | Equal variance not assumed. Comparison of WASI full IQ cases and controls | 2-Sided | Superiority or Other (legacy) |
| t-test, 2 sided | .853 | Equal variance not assumed. Comparison of CTMT global composite score between cases and controls | 2-Sided | Superiority or Other (legacy) |
| t-test, 2 sided | .001 | Equal variance not assumed. Comparison of BRIEF BRI cases and controls | 2-Sided | Superiority or Other (legacy) |
| t-test, 2 sided | <.001 | Equal variances not assumed. Comparison of BRIEF MI cases and controls | 2-Sided | Superiority or Other (legacy) |
| t-test, 2 sided | <0.001 | Equal variances not assumed. Comparison of BRIEF GEC between cases and controls. | 2-Sided | Superiority or Other (legacy) |