Summary of Study ST000877

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000608. The data can be accessed directly via it's Project DOI: 10.21228/M83105 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST000877
Study TitleMicronutrient deficiencies, environmental exposures and severe malaria: Risk factors for adverse neurodevelopmental outcomes in Ugandan children
Study TypeUntargeted high-resolution mass spectrometry profiling
Study SummaryMicronutrient deficiencies and environmental exposures have been to known to adversely impact brain and nervous system functions in adults and children worldwide. However, few studies have examined the short and long-term impact of these risk factors on neurodevelopmental outcomes in children in low-income countries, where the effects are likely to be more pronounced due to limited resources for monitoring and insufficient regulations. Biological risk factors of relevance include micronutrient deficiencies such as zinc and exposure to heavy metals such as lead and mercury. Studies have suggested an association between neurodevelopmental impairment and micronutrient deficiency as well as exposure to a number of heavy metals and environmental toxins. Moreover, findings also suggest that risk factors for adverse developmental outcomes that are independently significant may have the potential for causing cumulative increases in adverse effects. In Sub-Saharan Africa, severe malaria is a leading risk factor for long-term neurocognitive impairment in children. Zinc deficiency or exposure to heavy metals could influence risk of severe malaria, modify the risk of neurocognitive impairment in children with severe malaria, or independently affect risk of neurocognitive impairment. Untargeted analyses for potential environmental exposures or metabolomic changes in children with cerebral malaria vs. without cognitive impairment or in children with higher vs. lower cognitive scores, could also identify new risk factors for neurodevelopmental impairment in Ugandan children with cerebral malaria.In our completed study in Kampala, we assessed neurologic and developmental impairment in children with cerebral malaria [CM] or severe malarial anemia [SMA], as compared to health community children from the same extended household as the children with CM or SMA. As an extension of this study, we are interested in determining levels of micronutrients such as zinc in the population, and in addition, determining exposure levels of heavy metals (lead, mercury, copper, manganese etc.) in samples collected from children with severe malaria and community controls. The primary hypotheses of this study is that nutrient deficiencies or exposure to heavy metals influence short and long term neurocognitive outcomes in healthy community children and in children with severe malaria, and that children with cerebral malaria have specific metabolomic changes that relate to long-term neurocognitive impairment. The specific aims of our study are:Aim 1: To determine levels of zinc, heavy metals, and biomarkers associated with inflammation in children presenting with different forms of severe malaria (SM) and in healthy community children (CC). The working hypothesis of this aim is that 1) children with SM will have lower zinc levels compared to CC; 2) children with SM will present with higher toxic metal exposure and higher levels of biomarkers associated with inflammation than CC.Aim 2: To investigate how micronutrient deficiency, toxic metal exposure and inflammatory biomarkers affect short and long term neurodevelopmental outcomes and growth in children with severe malaria and community children (CC).The working hypothesis of this aim is that the lower levels of zinc, and presence of toxic metals in high concentrations will independently contribute to worsening neurodevelopmental outcomes and worsening growth over time in children with severe malaria and in community children. An alternate hypothesis is that micronutrient deficiency, toxic metal exposure and inflammatory states may interact with each other and with severe malaria to produce greater neurodevelopmental impairment, i.e., that the contribution is not independent but interactive.Aim 3: To determine whether the CSF metabolome differs according to level of neurodevelopmental impairment in children with cerebral malaria. The working hypothesis of this aim is that neurodevelopmental impairment in children with cerebral malaria is associated with changes in the CSF metabolome.
Institute
Emory University
DepartmentSchool of Medicine, Division of Pulmonary, Allergy, Critical Care Medicine
LaboratoryClincal Biomarkers Laboratory
Last NameWalker
First NameDouglas
Address615 Michael St. Ste 225, Atlanta, GA, 30322, USA
Emaildouglas.walker@emory.edu
Phone(404) 727 5984
Submit Date2017-09-27
Total Subjects141
Study CommentsCSF pools from elderly individuals included for QA/QC. Study specific pools were not created due to limited sample volumes provided (<100uL).
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Chear StudyYes
Analysis Type DetailLC-MS
Release Date2021-08-31
Release Version1
Douglas Walker Douglas Walker
https://dx.doi.org/10.21228/M83105
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR000608
Project DOI:doi: 10.21228/M83105
Project Title:Micronutrient deficiencies, environmental exposures and severe malaria: Risk factors for adverse neurodevelopmental outcomes in Ugandan children
Project Type:NIH/NINDS R01 NS055349
Project Summary:Micronutrient deficiencies and environmental exposures have been to known to adversely impact brain and nervous system functions in adults and children worldwide. However, few studies have examined the short and long-term impact of these risk factors on neurodevelopmental outcomes in children in low-income countries, where the effects are likely to be more pronounced due to limited resources for monitoring and insufficient regulations. Biological risk factors of relevance include micronutrient deficiencies such as zinc and exposure to heavy metals such as lead and mercury. Studies have suggested an association between neurodevelopmental impairment and micronutrient deficiency as well as exposure to a number of heavy metals and environmental toxins. Moreover, findings also suggest that risk factors for adverse developmental outcomes that are independently significant may have the potential for causing cumulative increases in adverse effects. In Sub-Saharan Africa, severe malaria is a leading risk factor for long-term neurocognitive impairment in children. Zinc deficiency or exposure to heavy metals could influence risk of severe malaria, modify the risk of neurocognitive impairment in children with severe malaria, or independently affect risk of neurocognitive impairment. Untargeted analyses for potential environmental exposures or metabolomic changes in children with cerebral malaria vs. without cognitive impairment or in children with higher vs. lower cognitive scores, could also identify new risk factors for neurodevelopmental impairment in Ugandan children with cerebral malaria.In our completed study in Kampala, we assessed neurologic and developmental impairment in children with cerebral malaria [CM] or severe malarial anemia [SMA], as compared to health community children from the same extended household as the children with CM or SMA. As an extension of this study, we are interested in determining levels of micronutrients such as zinc in the population, and in addition, determining exposure levels of heavy metals (lead, mercury, copper, manganese etc.) in samples collected from children with severe malaria and community controls. The primary hypotheses of this study is that nutrient deficiencies or exposure to heavy metals influence short and long term neurocognitive outcomes in healthy community children and in children with severe malaria, and that children with cerebral malaria have specific metabolomic changes that relate to long-term neurocognitive impairment. The specific aims of our study are:Aim 1: To determine levels of zinc, heavy metals, and biomarkers associated with inflammation in children presenting with different forms of severe malaria (SM) and in healthy community children (CC). The working hypothesis of this aim is that 1) children with SM will have lower zinc levels compared to CC; 2) children with SM will present with higher toxic metal exposure and higher levels of biomarkers associated with inflammation than CC.Aim 2: To investigate how micronutrient deficiency, toxic metal exposure and inflammatory biomarkers affect short and long term neurodevelopmental outcomes and growth in children with severe malaria and community children (CC).The working hypothesis of this aim is that the lower levels of zinc, and presence of toxic metals in high concentrations will independently contribute to worsening neurodevelopmental outcomes and worsening growth over time in children with severe malaria and in community children. An alternate hypothesis is that micronutrient deficiency, toxic metal exposure and inflammatory states may interact with each other and with severe malaria to produce greater neurodevelopmental impairment, i.e., that the contribution is not independent but interactive.Aim 3: To determine whether the CSF metabolome differs according to level of neurodevelopmental impairment in children with cerebral malaria. The working hypothesis of this aim is that neurodevelopmental impairment in children with cerebral malaria is associated with changes in the CSF metabolome.
Institute:Emory University
Department:Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine
Laboratory:Clinical Biomarkers Laboratory
Last Name:Walker
First Name:Douglas
Address:615 Michael St. Ste 225, Atlanta, GA, 30322, USA
Email:douglas.walker@emory.edu
Phone:(404) 727 5984
Funding Source:NIEHS ES026560
Contributors:Chandy C. John, Indiana University School of Medicine; Dibyadyuti Datta, Indiana University; Robert Opoka, Makerere University-Mulago Hospital; Dean P. Jones, Emory University School of Medicine; Karan Uppal, Emory University School of Medicine

Subject:

Subject ID:SU000911
Subject Type:Cerebrospinal Fluid
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:Pediatric samples
Human Trial Type:Observational
Species Group:Mammals

Factors:

Subject type: Cerebrospinal Fluid; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Sample Type
SA050837chearplasma_2cCHEAR Plasma
SA050838chearplasma_3aCHEAR Plasma
SA050839chearplasma_2bCHEAR Plasma
SA050840chearplasma_2aCHEAR Plasma
SA050841chearplasma_1dCHEAR Plasma
SA050842chearplasma_3bCHEAR Plasma
SA050843chearplasma_3dCHEAR Plasma
SA050844chearplasma_4cCHEAR Plasma
SA050845chearplasma_4dCHEAR Plasma
SA050846chearplasma_4bCHEAR Plasma
SA050847chearplasma_4aCHEAR Plasma
SA050848chearplasma_1cCHEAR Plasma
SA050849chearplasma_3cCHEAR Plasma
SA050850chearplasma_2dCHEAR Plasma
SA050851chearplasma_1aCHEAR Plasma
SA050852chearplasma_1bCHEAR Plasma
SA050853csfpool_4dCSF Pool
SA050854csfpool_4cCSF Pool
SA050855csfpool_2eCSF Pool
SA050856csfpool_4aCSF Pool
SA050857csfpool_3cCSF Pool
SA050858csfpool_2fCSF Pool
SA050859csfpool_1eCSF Pool
SA050860csfpool_2aCSF Pool
SA050861csfpool_2bCSF Pool
SA050862csfpool_1fCSF Pool
SA050863csfpool_1aCSF Pool
SA050864csfpool_3dCSF Pool
SA050865csfpool_4bCSF Pool
SA050866csfpool_2cCSF Pool
SA050867csfpool_1bCSF Pool
SA050868csfpool_3fCSF Pool
SA050869csfpool_3eCSF Pool
SA050870csfpool_4fCSF Pool
SA050871csfpool_4eCSF Pool
SA050872csfpool_1dCSF Pool
SA050873csfpool_1cCSF Pool
SA050874csfpool_3bCSF Pool
SA050875csfpool_3aCSF Pool
SA050876csfpool_2dCSF Pool
SA050877C-XBVS6-CF-00CSF Study Sample
SA050878C-XBXF3-CF-00CSF Study Sample
SA050879C-XCU28-CF-00CSF Study Sample
SA050880C-X7R50-CF-00CSF Study Sample
SA050881C-XB7F6-CF-00CSF Study Sample
SA050882C-XA7K7-CF-00CSF Study Sample
SA050883C-XAKS9-CF-00CSF Study Sample
SA050884C-XA870-CF-00CSF Study Sample
SA050885C-X7WK7-CF-00CSF Study Sample
SA050886C-XLGH4-CF-00CSF Study Sample
SA050887C-XR6V7-CF-00CSF Study Sample
SA050888C-XR6R6-CF-00CSF Study Sample
SA050889C-XQQ05-CF-00CSF Study Sample
SA050890C-XS193-CF-00CSF Study Sample
SA050891C-XSRV6-CF-00CSF Study Sample
SA050892C-XUWS3-CF-00CSF Study Sample
SA050893C-XUJF5-CF-00CSF Study Sample
SA050894C-XTRX9-CF-00CSF Study Sample
SA050895C-XPYG9-CF-00CSF Study Sample
SA050896C-XP6C3-CF-00CSF Study Sample
SA050897C-XGTT5-CF-00CSF Study Sample
SA050898C-XEA72-CF-00CSF Study Sample
SA050899C-XDCN1-CF-00CSF Study Sample
SA050900C-XHD99-CF-00CSF Study Sample
SA050901C-XKRU6-CF-00CSF Study Sample
SA050902C-XM3V1-CF-00CSF Study Sample
SA050903C-XM0D3-CF-00CSF Study Sample
SA050904C-X7AU7-CF-00CSF Study Sample
SA050905C-XCVE5-CF-00CSF Study Sample
SA050906C-X70K6-CF-00CSF Study Sample
SA050907C-WXAL5-CF-00CSF Study Sample
SA050908C-WX0F5-CF-00CSF Study Sample
SA050909C-WWY21-CF-00CSF Study Sample
SA050910C-WXGE4-CF-00CSF Study Sample
SA050911C-WXJQ5-CF-00CSF Study Sample
SA050912C-X0LF4-CF-00CSF Study Sample
SA050913C-WYEH8-CF-00CSF Study Sample
SA050914C-WXNN7-CF-00CSF Study Sample
SA050915C-WW0Q4-CF-00CSF Study Sample
SA050916C-WV7M8-CF-00CSF Study Sample
SA050917C-WRW40-CF-00CSF Study Sample
SA050918C-WQZA0-CF-00CSF Study Sample
SA050919C-WPSW1-CF-00CSF Study Sample
SA050920C-WRZP5-CF-00CSF Study Sample
SA050921C-WSMA8-CF-00CSF Study Sample
SA050922C-WUS96-CF-00CSF Study Sample
SA050923C-WTKE9-CF-00CSF Study Sample
SA050924C-X0RN0-CF-00CSF Study Sample
SA050925C-X1BV7-CF-00CSF Study Sample
SA050926C-X6NS0-CF-00CSF Study Sample
SA050927C-X66K2-CF-00CSF Study Sample
SA050928C-X65W7-CF-00CSF Study Sample
SA050929C-X6UX2-CF-00CSF Study Sample
SA050930C-XUXR5-CF-00CSF Study Sample
SA050931C-Z6TH7-CF-00CSF Study Sample
SA050932C-Z9710-CF-00CSF Study Sample
SA050933C-X5XU8-CF-00CSF Study Sample
SA050934C-X5P15-CF-00CSF Study Sample
SA050935C-X2G11-CF-00CSF Study Sample
SA050936C-X2C64-CF-00CSF Study Sample
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Collection:

Collection ID:CO000905
Collection Summary:Please contact project PI, Chandy John (chjohn@iu.edu), for sample collection details.
Sample Type:Cerebrospinal Fluid

Treatment:

Treatment ID:TR000925
Treatment Summary:Samples were received frozen in aliquouts of <100uL. Freeze-thaw history for study samples prior to receipt by the Emory URR is provided in the Study Design section. Prior to analysis, samples were thawed and prepared for HRM analysis using the standard protocols described in the Sample Preparation section.

Sample Preparation:

Sampleprep ID:SP000918
Sampleprep Summary:Samples were prepared for metabolomics analysis using established methods (Johnson et al. (2010). Analyst; Go et al. (2015). Tox Sci). Prior to analysis, urine aliquots were removed from storage at -80°C and thawed on ice. Each cryotube was then vortexed briefly to ensure homogeneity, and 50 μL was transferred to a clean microfuge tube. Immediately after, the urine was treated with 100 μL of ice-cold LC-MS grade acetonitrile (Sigma Aldrich) containing 2.5 μL of internal standard solution with eight stable isotopic chemicals selected to cover a range of chemical properties. Following addition of acetonitrile, urine was equilibrated for 30 min on ice, upon which precipitated proteins were removed by centrifuge (16.1 ×g at 4°C for 10 min). The resulting supernatant (100 μL) was removed, added to a low volume autosampler vial and maintained at 4°C until analysis (<22 h).
Sampleprep Protocol ID:HRM_SP_082016_01
Sampleprep Protocol Filename:EmoryUniversity_HRM_SP_082016_01.pdf
Sampleprep Protocol Comments:Date effective: 30 July 2016
Extraction Method:2:1 acetonitrile: sample followed by vortexing and centrifugation
Sample Spiking:2.5 uL [13C6]-D-glucose, [15N,13C5]-L-methionine, [13C5]-L-glutamic acid, [15N]-L-tyrosine, [3,3-13C2]-cystine, [trimethyl-13C3]-caffeine, [U-13C5, U-15N2]-L-glutamine, [15N]-indole

Combined analysis:

Analysis ID AN001426 AN001427
Analysis type MS MS
Chromatography type HILIC Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 Thermo Dionex Ultimate 3000
Column Waters XBridge Amide (50 x 2.1mm,2.5um) Thermo Higgins C18 (50 x 2.1mm,3um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive HF hybrid Orbitrap Thermo Q Exactive HF hybrid Orbitrap
Ion Mode POSITIVE NEGATIVE
Units Peak intensity Peak intensity

Chromatography:

Chromatography ID:CH000997
Chromatography Summary:The HILIC column is operated parallel to reverse phase column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of HILIC separation method, the MS is operated in positive ion mode and 10 μL of sample is injected onto the HILIC column while the reverse phase column is flushing with wash solution. Flow rate is maintained at 0.35 mL/min until 1.5 min, increased to 0.4 mL/min at 4 min and held for 1 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 2% formic acid (v/v) in LC-MS grade water. Initial mobile phase conditions are 22.5% A, 75% B, 2.5% C hold for 1.5 min, with linear gradient to 77.5% A, 20% B, 2.5% C at 4 min, hold for 1 min, resulting in a total analytical run time of 5 min. During the flushing phase (reverse phase analytical separation), the HILIC column is equilibrated with a wash solution of 77.5% A, 20% B, 2.5% C.
Methods ID:2% formic acid in LC-MS grade water
Methods Filename:20160920_posHILIC120kres5min_ESI_c18negwash.meth
Chromatography Comments:Triplicate injections for each chromatography mode
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Waters XBridge Amide (50 x 2.1mm,2.5um)
Column Temperature:60C
Flow Gradient:A= water, B= acetontrile, C= 2% formic acid in water; 22.5% A, 75% B, 2.5% C hold for 1.5 min, linear gradient to 77.5% A, 20% B, 2.5% C at 4 min, hold for 1 min
Flow Rate:0.35 mL/min for 1.5 min; linear increase to 0.4 mL/min at 4 min, hold for 1 min
Sample Injection:10 uL
Solvent A:100% water
Solvent B:100% acetonitrile
Analytical Time:5 min
Sample Loop Size:15 uL
Sample Syringe Size:100 uL
Chromatography Type:HILIC
  
Chromatography ID:CH000998
Chromatography Summary:The C18 column is operated parallel to the HILIC column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of the C18 method, the MS is operated in negative ion mode and 10 μL of sample is injected onto the C18 column while the HILIC column is flushing with wash solution. Flow rate is maintained at 0.4 mL/min until 1.5 min, increased to 0.5 mL/min at 2 min and held for 3 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 10mM ammonium acetate in LC-MS grade water. Initial mobile phase conditions are 60% A, 35% B, 5% C hold for 0.5 min, with linear gradient to 0% A, 95% B, 5% C at 1.5 min, hold for 3.5 min, resulting in a total analytical run time of 5 min. During the flushing phase (HILIC analytical separation), the C18 column is equilibrated with a wash solution of 0% A, 95% B, 5% C until 2.5 min, followed by an equilibration solution of 60% A, 35% B, 5% C for 2.5 min.
Methods ID:10mM ammonium acetate in LC-MS grade water
Methods Filename:20160920_negC18120kres5min_ESI_HILICposwash.meth
Chromatography Comments:Triplicate injections for each chromatography mode
Instrument Name:Thermo Dionex Ultimate 3000
Column Name:Thermo Higgins C18 (50 x 2.1mm,3um)
Column Temperature:60C
Flow Gradient:A= water, B= acetontrile, C= 10mM ammonium acetate in water; 60% A, 35% B, 5% C hold for 0.5 min, linear gradient to 0% A, 95% B, 5% C at 1.5 min, hold for 3 min
Flow Rate:0.4 mL/min for 1.5 min; linear increase to 0.5 mL/min at 2 min held for 3 min
Sample Injection:10 uL
Solvent A:100% water
Solvent B:100% acetonitrile
Analytical Time:5 min
Sample Loop Size:15 uL
Sample Syringe Size:100 uL
Chromatography Type:Reversed phase

MS:

MS ID:MS001316
Analysis ID:AN001426
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
Ion Mode:POSITIVE
Capillary Temperature:250C
Collision Gas:N2
Dry Gas Flow:45
Dry Gas Temp:150C
Mass Accuracy:< 3ppm
Spray Voltage:+3500
Activation Parameter:5e5
Activation Time:118ms
Interface Voltage:S-Lens RF level= 55
Resolution Setting:120,000
Scanning Range:85-1275
Analysis Protocol File:EmoryUniversity_HRM_QEHF-MS_092017_v1.pdf
  
MS ID:MS001317
Analysis ID:AN001427
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
Ion Mode:NEGATIVE
Capillary Temperature:250C
Collision Gas:N2
Dry Gas Flow:45
Dry Gas Temp:150C
Mass Accuracy:< 3ppm
Spray Voltage:-4000
Activation Parameter:5e5
Activation Time:118ms
Interface Voltage:S-Lens RF level= 55
Resolution Setting:120,000
Scanning Range:85-1275
Analysis Protocol File:EmoryUniversity_HRM_QEHF-MS_092017_v1.pdf
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