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Structure Identification Using High Resolution Mass Spectrometry Data and the EPA CompTox Dashboard

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The iCSS CompTox Dashboard is a publicly accessible dashboard provided by the National Center for Computation Toxicology at the US-EPA. It serves a number of purposes, including providing a chemistry database underpinning many of our public-facing projects (e.g. ToxCast and ExpoCast). The available data and searches provide a valuable path to structure identification using mass spectrometry as the source data. With an underlying database of over 720,000 chemicals, the dashboard has already been used to assist in identifying chemicals present in house dust. However, it can also be applied to many other purposes, e.g., the identification of agrochemicals in waste streams. This presentation will provide a review of the EPA’s platform and underlying algorithms used for the purpose of compound identification using high-resolution mass spectrometry data. In order to examine its performance for structure identification, especially in terms of rank-ordering database hits, we have compared it with the ChemSpider database, a well-regarded public database that has become one of the community standards for structure identification. The study has shown that the CompTox Dashboard outperforms ChemSpider in terms of structure identification and ranking providing improved outcomes for mass spectrometry analysis of “known unknowns”.

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Structure Identification Using High Resolution Mass Spectrometry Data and the EPA CompTox Dashboard

  1. 1. Structure Identification Using High Resolution Mass Spectrometry Data and the EPA CompTox Dashboard Antony J. Williams, Andrew McEachran, Chris Grulke, Elin Ulrich, Jennifer Smith, Jeff Edwards and Jon Sobus, November 2-3, 2016 SWEMSA 2016 http://www.orcid.org/0000-0002-2668-4821 The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA
  2. 2. Who is NCCT? • National Center for Computational Toxicology – part of EPA’s Office of Research and Development • Research driven by EPA’s Chemical Safety for Sustainability Research Program – Develop new approaches to evaluate the safety of chemicals – Integrate advances in biology, biotechnology, chemistry, exposure science and computer science • Goal - To identify chemical exposures that may disrupt biological processes and cause adverse outcomes. 1
  3. 3. Our Dashboard Applications • Some of our Web-based Applications 2
  4. 4. Introducing Our Latest Dashboard https://comptox.epa.gov 3 • >720,000 chemicals • >14 years assembling data
  5. 5. Bisphenol A 4
  6. 6. Physicochemical Properties 5
  7. 7. ToxCast Bioassay Screening Data Useful Meta Data 6
  8. 8. Functional Use and Composition VERY Useful Meta Data 7
  9. 9. Dashboard: External Links to Analytical Methods and Data 8
  10. 10. National Environmental Methods Index 9
  11. 11. RSC Analytical Abstracts 10
  12. 12. For_IDENT and MONA 11
  13. 13. Previous Work with Suspect-Screening ONE ASPECT of the dashboard is to support Non-targeted Analysis
  14. 14. Rank-Ordering of “Known-Unknowns” using ChemSpider 13
  15. 15. Some history… • 2007 A Hobby Project 14
  16. 16. Some history… • 2007 A Hobby Project • 2009 ChemSpider Acquired 15
  17. 17. Some history… • 2007 A Hobby Project • 2009 ChemSpider Acquired • May 2015 Joined EPA – what we are showing is very new 16
  18. 18. Advanced MS Searches 17
  19. 19. Monoisotopic Mass Search 18 Found 344 results for '215.096 ± 0.005 amu'
  20. 20. Download to Excel 19
  21. 21. Download as SDF file 20
  22. 22. Formula Search 21 Found 8 results for 'C8H14ClN5'
  23. 23. Does the Dashboard Add Value? 22 721k structures
  24. 24. Does the Dashboard Add Value? • Remember: – Focus on high quality data and curation – Data sources include EPA data sources and a focus on environmental chemistry • No “dilution” by chemical vendors 23
  25. 25. Dilution Example… Morphine Skeleton 24
  26. 26. Bisphenol A as an example ChemSpider: 1564 Structures 25
  27. 27. Bisphenol A as an example Dashboard: 215 Structures 26
  28. 28. ChemSpider 6926 Results!!! 27 Tacedinaline Methyl Red C.I Disperse Yellow 3
  29. 29. Using Meta-Data to Sort Candidates 28 Anti-cancer Drug Microbiological Indicator Dye Textile/Product Dye
  30. 30. Same top hits – different ranking 90 hits only versus 6926 hits 29 18 17 4Tacedinaline Methyl Red C.I Disperse Yellow 3
  31. 31. Chemical Identification Dashboard vs ChemSpider Sorted by number of references (ChemSpider) or data sources (Dashboard) Monoisotopic Mass (+/- 0.005 amu) Search Position of compound sorted Source of List # of Compounds Search Tool Mean Position Median Position #1 #2 #3 #4 #5+ McEachran et al Wastewater 34 ChemSpider 1.8 1 28 5 0 0 1 Dashboard 1.3 1 31 2 0 0 1 Misc. NTA Compounds 13 ChemSpider 2 1 7 5 0 0 1 Dashboard 1.7 1 10 2 0 0 1 Bade et al (2016) 19 ChemSpider 2.1 1 11 2 5 0 1 Dashboard 1.6 1 12 3 3 1 0 Rager et al (2016) 24 ChemSpider 2.25 1 15 2 1 2 4 Dashboard 1.08 1 22 2 0 0 0
  32. 32. Dashboard vs ChemSpider Ranking Summary Mass-based Searching Formula Based Searching Dashboard ChemSpider Dashboard ChemSpider Cumulative Average Position 1.3 2.2 1.2 1.4 % in #1 Position 85% 70% 88% 80% • Selected peer-reviewed publications • 162 total individual chemicals in search
  33. 33. The Confusion of Chemicals… Valid CAS-substance? Monoisotopic Mass Formula Parent structure (no stereo, desalted)  Resolve CAS-structure mappings for accurate data mapping  Collapse sphere to collect all data at parent structure-formula level DSSTox_v2 Database & Cheminformatics Layer many:1 • Deleted CAS • Invalid CAS • Salt forms • Complex forms • Hydrate forms • Approx mappings to mixtures • Approx mappings to ill- defined substances • Stereoisomers • Unresolved tautomers CAS2 ? CAS5 ? CAS3 ? CAS1 ? CAS4 ?NOCAS? Data1 Data2 Data3 Data4 Data5 Data6 Data7 Data8 Data9 CAS-Structure “Sphere of Confusion”
  34. 34. DSSTox List Curation Tool Conflicts binned to facilitate curation
  35. 35. Helping to Curate Data • We are helping to Curate Data (prior to linking from our dashboard) • Our discussions with Thomas and team – “We all agree it is hard!” 34
  36. 36. Helping to Curate Data • We are helping to Curate Data (prior to linking from our dashboard) • Our discussions with Thomas and team – “We all agree it is hard!” • Approx. 80% of STOFF-IDENT is done… 35
  37. 37. Helping to Curate Data • We are helping to Curate Data (prior to linking from our dashboard) • Our discussions with Thomas and team – “We all agree it is hard!” • Approx. 80% of STOFF-IDENT is done… 36
  38. 38. Curating on CASRNs is DIFFICULT • 36861-47-9 : SI00004220 • 38102-62-4 : SI00008957 37
  39. 39. Collisions in CAS Numbers 38
  40. 40. Active and Deleted CASRN 39
  41. 41. But there are MANY CASRNs! • http://web.stanford.edu/group/swain/cinf/c asreg/snumber.html 40
  42. 42. How Bad Can It Get?? 41
  43. 43. How Bad Can It Get? This one is 316 Deleted CASRN 42
  44. 44. Helping to Curate Data • We are missing 159 CAS Numbers listed in STOFF-IDENT • Work on curating and mapping MASSBANK is underway. Much bigger!! Way more work
  45. 45. Our OPEN Data is available… • Various types of data at FTP download site: ftp://newftp.epa.gov/COMPTOX/Sustainable_Chemistry_ Data/Chemistry_Dashboard 44
  46. 46. Data Availability • The data are now available in METLIN • Available in MetFrag (alpha) and in testing. 45
  47. 47. Coming December 2016 Batch Searching Names/CASRNs • What are these chemicals? 46
  48. 48. Coming December 2016 Batch Searching… 47
  49. 49. Coming December 2016 Download to Excel 48
  50. 50. In-testing 49
  51. 51. Metadata included for Ranking 50
  52. 52. Need for “MS-Ready Structures” 51
  53. 53. “QSAR-Ready Structures” • For the purpose of building QSAR Models we already “standardize” structures – Desalt/Neutralize – Desolvate – Remove stereochemistry • Some minor tweaks gets us “MS-ready Structures”. ALREADY in our database. 52
  54. 54. “QSAR-Ready Structures” • Mass and Formula-based searches will be based on MS-ready structures but connected to the original chemical (with name, CAS, rank ordering) • MS-ready structures and substance mappings will be available as Open Data 53
  55. 55. Rank-Ordering – incl. PubChem 54
  56. 56. Future Work • Continue to research rank-ordering approaches • Working on “retention time prediction” • Search for adducts (+Na, +K, +NH4) and handle decarboxylation, loss of water etc • Additional links to methods – CDC NIOSH • Expand link outs to Mass Spec databases – Thermo’s mzCloud, Massbank, etc. • Predicting metabolites and degradants • Optimize web services for the community 55
  57. 57. Conclusions • Only 1 aspect of the dashboard is focused on MS – to support the EPA NTA Trial underway • We should work on data curation TOGETHER! • We are “part” of the solution. Our Open Data and Open Services should be of value. 56
  58. 58. Acknowledgements EPA NCCT Chris Grulke Jeff Edwards Ann Richard Jennifer Smith Andrew McEachran* EPA NERL Jon Sobus Seth Newton Elin Ulrich * = ORISE Participant

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