Summary of Study ST002818

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 PR001762. The data can be accessed directly via it's Project DOI: 10.21228/M8ZB1D 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 IDST002818
Study TitleEvaluation of Novel Candidate Filtration Markers from a Global Metabolomics Discovery for Glomerular Filtration Rate Estimation (ALTOLD)
Study SummaryBackground: Creatinine and cystatin-C are recommended for estimating glomerular filtration rate (eGFR) but accuracy is suboptimal. Using untargeted metabolomics data, we sought to identify candidate filtration markers using a novel approach based on their maximal joint association with measured GFR (mGFR) with flexibility to consider their biological and chemical properties later. Methods: We analyzed metabolites measured in seven diverse studies of 2,851 participants on the Metabolon H4 platform that had Pearson correlations with log mGFR <-0.5. We used a stepwise approach to develop models to estimate mGFR including two to 15 metabolites with and without inclusion of creatinine and demographics. We then selected candidate filtration markers from those metabolites found >20% in models that did not demonstrate substantial overfitting in cross-validation and with small (<0.1 in absolute value) coefficients for demographics. Results: In total, 456 named metabolites were present in all studies, and 36 had correlations <-0.5 with mGFR. We developed 2,225 models including these metabolites; all had lower RMSEs and smaller coefficients for demographic variables compared to estimates using untargeted creatinine. Cross-validated RMSEs (0.187-0.213) were similar to original RMSEs for models with ≤ 10 metabolites. Our criteria identified 17 metabolites, including 12 new candidate filtration markers. Conclusion: We identified candidate metabolites with maximal joint association with mGFR and minimal association with demographic variables across varied clinical settings. Future analyses will assess metabolite biological and chemical characteristics in the path towards development of a panel eGFR that is more accurate and less reliant on demographic variables than current eGFR. ACRONYMS AASKG1: African American Study of Kidney (patient data at G1 visit). ALTOLD: Assessing Long Term Outcomes in Living Kidney Donors study. MDRD: The Modification of Diet in Renal Disease study.
Institute
Tufts Medical Center
DepartmentNephrology
Last NameInker
First NameLesley
Address800 Washington Street
EmailLesley.Inker@tuftsmedicine.org
Phone6176368783
Submit Date2023-06-29
Analysis Type DetailOther
Release Date2023-09-06
Release Version1
Lesley Inker Lesley Inker
https://dx.doi.org/10.21228/M8ZB1D
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001762
Project DOI:doi: 10.21228/M8ZB1D
Project Title:Improving kidney function assessment in health and disease
Project Summary:Use results from a global metabolomics platform with existing measured GFR assessments to identify a set of markers from which to develop a highly accurate targeted mass spectrometry multiplex assay
Institute:Tufts Medical Center
Department:Nephrology
Laboratory:Metabolon; University of Minnesota
Last Name:Inker
First Name:Lesley
Address:800 Washington Street, Boston, Massachusetts, 02111, USA
Email:Lesley.Inker@tuftsmedicine.org
Phone:6176368783
Funding Source:NIDDK

Subject:

Subject ID:SU002927
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:18 and older
Gender:Male and female

Factors:

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

mb_sample_id local_sample_id study
SA3026426568695ALTOLD
SA3026436568694ALTOLD
SA3026446568693ALTOLD
SA3026456568696ALTOLD
SA3026466568698ALTOLD
SA3026476568700ALTOLD
SA3026486568699ALTOLD
SA3026496568692ALTOLD
SA3026506568697ALTOLD
SA3026516568691ALTOLD
SA3026526568686ALTOLD
SA3026536568685ALTOLD
SA3026546568684ALTOLD
SA3026556568687ALTOLD
SA3026566568688ALTOLD
SA3026576568690ALTOLD
SA3026586568689ALTOLD
SA3026596568701ALTOLD
SA3026606568702ALTOLD
SA3026616568714ALTOLD
SA3026626568713ALTOLD
SA3026636568712ALTOLD
SA3026646568715ALTOLD
SA3026656568716ALTOLD
SA3026666568719ALTOLD
SA3026676568718ALTOLD
SA3026686568711ALTOLD
SA3026696568710ALTOLD
SA3026706568705ALTOLD
SA3026716568704ALTOLD
SA3026726568703ALTOLD
SA3026736568706ALTOLD
SA3026746568707ALTOLD
SA3026756568709ALTOLD
SA3026766568708ALTOLD
SA3026776568683ALTOLD
SA3026786568682ALTOLD
SA3026796568659ALTOLD
SA3026806568658ALTOLD
SA3026816568657ALTOLD
SA3026826568660ALTOLD
SA3026836568661ALTOLD
SA3026846568663ALTOLD
SA3026856568662ALTOLD
SA3026866568656ALTOLD
SA3026876568655ALTOLD
SA3026886568650ALTOLD
SA3026896568649ALTOLD
SA3026906568648ALTOLD
SA3026916568651ALTOLD
SA3026926568652ALTOLD
SA3026936568654ALTOLD
SA3026946568653ALTOLD
SA3026956568664ALTOLD
SA3026966568665ALTOLD
SA3026976568677ALTOLD
SA3026986568676ALTOLD
SA3026996568675ALTOLD
SA3027006568678ALTOLD
SA3027016568679ALTOLD
SA3027026568681ALTOLD
SA3027036568680ALTOLD
SA3027046568674ALTOLD
SA3027056568673ALTOLD
SA3027066568668ALTOLD
SA3027076568667ALTOLD
SA3027086568666ALTOLD
SA3027096568669ALTOLD
SA3027106568670ALTOLD
SA3027116568672ALTOLD
SA3027126568671ALTOLD
SA3027136568720ALTOLD
SA3027146568721ALTOLD
SA3027156568769ALTOLD
SA3027166568768ALTOLD
SA3027176568767ALTOLD
SA3027186568770ALTOLD
SA3027196568771ALTOLD
SA3027206568773ALTOLD
SA3027216568772ALTOLD
SA3027226568766ALTOLD
SA3027236568765ALTOLD
SA3027246568760ALTOLD
SA3027256568759ALTOLD
SA3027266568758ALTOLD
SA3027276568761ALTOLD
SA3027286568762ALTOLD
SA3027296568764ALTOLD
SA3027306568763ALTOLD
SA3027316568774ALTOLD
SA3027326568775ALTOLD
SA3027336568787ALTOLD
SA3027346568786ALTOLD
SA3027356568785ALTOLD
SA3027366568788ALTOLD
SA3027376568789ALTOLD
SA3027386568791ALTOLD
SA3027396568790ALTOLD
SA3027406568784ALTOLD
SA3027416568783ALTOLD
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Collection:

Collection ID:CO002920
Collection Summary:samples were obtained from NIDDK repository
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR002936
Treatment Summary:Samples were prepared using the automated MicroLab STAR® system from Hamilton Company. Several recovery standards were added prior to the first step in the extraction process for QC purposes. To remove protein, dissociate small molecules bound to protein or trapped in the precipitated protein matrix, and to recover chemically diverse metabolites, proteins were precipitated with methanol under vigorous shaking for 2 min (Glen Mills GenoGrinder 2000) followed by centrifugation. The resulting extract was divided into five fractions: two for analysis by two separate reverse phase (RP)/UPLC-MS/MS methods with positive ion mode electrospray ionization (ESI), one for analysis by RP/UPLC-MS/MS with negative ion mode ESI, one for analysis by HILIC/UPLC-MS/MS with negative ion mode ESI, and one sample was reserved for backup. Samples were placed briefly on a TurboVap® (Zymark) to remove the organic solvent. The sample extracts were stored overnight under nitrogen before preparation for analysis.

Sample Preparation:

Sampleprep ID:SP002933
Sampleprep Summary:All methods utilized a Waters ACQUITY ultra-performance liquid chromatography (UPLC) and a Thermo Scientific Q-Exactive high resolution/accurate mass spectrometer interfaced with a heated electrospray ionization (HESI-II) source and Orbitrap mass analyzer operated at 35,000 mass resolution. The sample extract was dried then reconstituted in solvents compatible to each of the four methods. Each reconstitution solvent contained a series of standards at fixed concentrations to ensure injection and chromatographic consistency. One aliquot was analyzed using acidic positive ion conditions, chromatographically optimized for more hydrophilic compounds. In this method, the extract was gradient eluted from a C18 column (Waters UPLC BEH C18-2.1x100 mm, 1.7 µm) using water and methanol, containing 0.05% perfluoropentanoic acid (PFPA) and 0.1% formic acid (FA). Another aliquot was also analyzed using acidic positive ion conditions, however it was chromatographically optimized for more hydrophobic compounds. In this method, the extract was gradient eluted from the same afore mentioned C18 column using methanol, acetonitrile, water, 0.05% PFPA and 0.01% FA and was operated at an overall higher organic content. Another aliquot was analyzed using basic negative ion optimized conditions using a separate dedicated C18 column. The basic extracts were gradient eluted from the column using methanol and water, however with 6.5mM Ammonium Bicarbonate at pH 8. The fourth aliquot was analyzed via negative ionization following elution from a HILIC column (Waters UPLC BEH Amide 2.1x150 mm, 1.7 µm) using a gradient consisting of water and acetonitrile with 10mM Ammonium Formate, pH 10.8. The MS analysis alternated between MS and data-dependent MSn scans using dynamic exclusion. The scan range varied slighted between methods but covered 70-1000 m/z. Raw data files are archived and extracted as described below

Combined analysis:

Analysis ID AN004586 AN004587 AN004588 AN004589
Analysis type MS MS MS MS
Chromatography type Reversed phase Reversed phase Reversed phase HILIC
Chromatography system Waters Acquity Waters Acquity Waters Acquity Waters Acquity
Column Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) Waters ACQUITY UPLC BEH Amide (150 x 2.1mm,1.7um)
MS Type ESI ESI ESI ESI
MS instrument type Orbitrap Orbitrap Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode POSITIVE POSITIVE NEGATIVE NEGATIVE
Units raw area counts rescaled to set the median equal to 1 raw area counts rescaled to set the median equal to 1 raw area counts rescaled to set the median equal to 1 raw area counts rescaled to set the median equal to 1

Chromatography:

Chromatography ID:CH003446
Chromatography Summary:Low pH polar (LC/MS Pos early)
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um)
Column Temperature:-
Flow Gradient:-
Flow Rate:-
Solvent A:-
Solvent B:-
Chromatography Type:Reversed phase
  
Chromatography ID:CH003447
Chromatography Summary:Low pH Lipophilic (LC/MS Pos late)
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um)
Column Temperature:-
Flow Gradient:-
Flow Rate:-
Solvent A:-
Solvent B:-
Chromatography Type:Reversed phase
  
Chromatography ID:CH003448
Chromatography Summary:High pH (LC/MS Neg)
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um)
Column Temperature:-
Flow Gradient:-
Flow Rate:-
Solvent A:-
Solvent B:-
Chromatography Type:Reversed phase
  
Chromatography ID:CH003449
Chromatography Summary:HILIC (LC/MS Polar Neg)
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC BEH Amide (150 x 2.1mm,1.7um)
Column Temperature:-
Flow Gradient:-
Flow Rate:-
Solvent A:-
Solvent B:-
Chromatography Type:HILIC

MS:

MS ID:MS004332
Analysis ID:AN004586
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Metabolon (LC/MS Pos early)
Ion Mode:POSITIVE
  
MS ID:MS004333
Analysis ID:AN004587
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Metabolon (LC/MS Pos late)
Ion Mode:POSITIVE
  
MS ID:MS004334
Analysis ID:AN004588
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Metabolon (LC/MS Neg)
Ion Mode:NEGATIVE
  
MS ID:MS004335
Analysis ID:AN004589
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Metabolon (LC/MS Polar)
Ion Mode:NEGATIVE
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