1. Global Biomarker Standardization Consortium
Chairs: Holly Soares, Henrik Zetterberg, Piotr Lewczuk

2. TEAM OBJECTIVES
To create a certified reference material (i.e. human CSF pools) that can use by assay developers to create a gold standard for absolute and accurate measures of CSF Aβ42 and T-Tau.
To create universal reference calibrators that can be used in the antibody independent reference method to measure absolute concentrations of CSF AB42 and T-tau
To create a large pool of quality control material that the end user lab could use to check assay precision.

3. Certified Reference Material
Many options
Immunodepleted matrix spiked in with endogenous peptide or engineered peptide
Matrix equivalent spiked in with endogeneous peptide or engineered peptide.
Native material (e.g. human CSF pools)
Team agreement
Human CSF pools of sufficient quantity to provide primarily assay developers for 1-3 years.
Action Item: companies to get answer specific questions

4. Questions for company
Where are companies (both IVD and pharma) getting as starting materials for both ab42 and tau?
How to get common starting point of the materials?
INNX-Manu able to report small overview presentation for next call; Source materials and share materials for next meeting
Would like to hear from all companies about what they can and can’t share to the group.
George Green to give update on outside 3rd party opportunity.
Henrik to give update on IFCC (?) from Dec. 16 (from JPMD mtg)

5. Issues
Does group scope include collection of CSF pool or stop at certified ref materials?
Cancel 19dec and meet next in Jan 2012
Holly to take first draft and send to all for input before we get those questions to IVD and pharma company permissions.
Henrik and Kaj to give overview of QC program.
Review process to take 3 weeks in one company’s estimate, thus attempt to get questions as quick as possible to enable internal company preparation and approval.

6. CRM Actions/notes 11/29/11
Henrik has submitted a proposal to IFCC to make reference material for analytes and it was approved.
IFCC would observe the project and IRMM would be actively involved as a partner that would guide the creation of the reference material.
IFCC requires a reference method.
The most feasible approach is to create a large pool and then test the pilot ref material for stability, homogeneity and stability.
Henrik will update team on IFCC and IRMM activities at December call.
Request more information from assay developers regarding reference materials
Manu (INNX/FBI) and Pankaj (MSD) to inquire on whether data can be shared
Holly to invite OCD/SBI and Roche to team discussions

7. Update QC program 11/29/11
Calibrators discussion will be tabled. And on the next call we should have a discussion to talk about the next steps there.
QC issues: currently there are a few efforts towards this end, Bob asked that perhaps on another call we could have a discussion of the QC programs.
Maria will schedule a webinar for later to do a good comparison between the two, the AA CSF QC and the German project of Piotr.

8. AGENDA 12 Dec 2011 Review of Objectives Review of Action items
Introduction additional assay manufacturers
USDS reference calibrator proposal
Next steps

9. Future Call Dates
Monday 12/12 - 6:30 am PST / 8:30 am CST / 9:30 am EST / 3:30 pm Sweden
Monday 12/19 - 6:30 am PST / 8:30 am CST / 9:30 am EST / 3:30 pm Sweden

10. Notes 18jan2012
Highlights:
Ways to std and measure use an independent method?
Where does/will certified human CSF reference material fit in ?
INNX uses human QC CSF material…
Set of questions to share with other companies? Similar or different?
Endogenous peptide or not?
Other methods used?
Source of peptides?
Source of polypropylene tubes?
Look at MindMap from Hugo for things to consider…
Next step: Henrik work stream follow-up on human Certified CSF reference materials
Rand Jenkins (PPD) –
update on calibrators: relook at vendor side and confirm info be getting from a certificate of analysis, std of lyophilized solvent into DMSO trichloro-ethanol, stock to dissolve primary, ammonium hydroxide also fine . . .
Multiplexed method of multiple forms of abeta has lead to some compromise to detect a lot of peptides, make compromise on ab42 detection to get the others included; he suggests that may want to go back and optimize just for ab42 and focus on that…

11. Notes 18jan2012 (2)
MS method can distinguish PTMs (e.g. methionine, etc)
Can perhaps monitor for degree of oxidation of ab42 in peptide but also hu CSF samples
Can use MS to tell us what else is in the synthetic products, pref by High Res MS to sequence and ID the types of impurities (degration products or synthesis by-products…)… suggest characterize and don’t take at face value what peptide vendors provide to customers…
MSD: will check internally to see what they can share about their approach
Next steps:
generate questions from INNX presentation,
get similar input from other assay companies and get broader view
Assemble list of rec’d suppliers for abeta1-42 peptide (process to QC their material)
Assemble list of rec’d PP tube suppliers (process to QC their material)
MS: abeta suppliers on a future call and tube manufactuers (PP) on future call…
French group working on paper in press for the PP tube, can we get pre-print or update to inform this GBSC team?
March 5, QC overview join this call… by Henrik etal

12. Notes 5apr2012 (1) Hear more from Henrik on IRMM
Reference methods and reference materials
Submit candidate methods and materials
Ingrid Zegrese (IRMM) will attend these meetings, and give presentation on IRMM
R-peptide appears preferred vendor for AB42 synthetic analyte
Propose to build an internal ab42 analog to compare normal hu CSF vs artificial CSF matrix
C13, n19 labeled to pick up difference in Mass Spec
Commutability test will be done within the IRMM process – statistical tests ?
Ingrid will be able to show examples from other programs
Guanidine HCl treatment to help strip away
Pilot SUH MS study (Henrik) of N= 50 CSF show good diagnostic discrimination, in contrast to Slemmon et al’s paper. MS AB42 method is still able to discriminate AD vs CTL (mild-mod Dementia, age matched controls)
U Penn (Les) (10/10) early AD vs age matched control

13. Notes 5apr2012 (2) Rand (PPD) proposal
To avoid storage issues, create artificial fresh CSF mix + DMSO AB42 to make calibrator
Add lipid perhaps, correct protein conc
Surrogate analytes with isobaric labeled analytes
Stability of component A (buffer salt solution), Buffered IgG/BSA
Plan to establish stability of AB42 in DMSO stocks
Human QCs will also be included
Next try to merge, cancel tomorrow’s call as Good Friday
Action items for next Joint Mtg
Excel spreadsheet comparing MS methods from Les
Henrik to review his RASAD presentation with the group
IRMM overview presentation from Ingrid
Henrik to present on IRMM project plan (assuming Ingrid has approved)