Automation and standardisation of NIPD

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1 Automation and standardisation of NIPD Tobias J. Legler Dept. of Transfusion Medicine, University Medical Center Göttingen Certified according to DIN ISO 9001:2000 SAFE FINAL GENERAL ASSEMBLYin TARRAGONA 29 th /30 th May 2008

2 SAFE: RHD NIPD Standardisation Questions 1. Which reference material of a higher order can we use to determine the analytical sensitivity of RHD NIPD? 2. Is there a reference measurement procedure? 3. Which is the diagnostic sensitivity and specificity of the most promising (automated) technology platforms compared with the current gold standard serology? 4. How can we test repeatability, consistency and uniformity in an external Quality Assurance scheme? 5. Which internal control can we use for RHD NIPD screening?

Is there a reference measurement procedure? 3.

3 RhD/SRY reference material of higher order Evelyn Tait Standards, Standardisation and Current Limitations of NIPD

4 Reference measurement procedure Workshop QIAampresults DSP Virus published Kit (Qiagen, Hilden,Germany), Legler Cat. TJ No. and SAFE partners: Prenat Diagn 2007;27:824-9 Mean pg/ml 4000 Details of protocols published Legler TJ and 3000SAFE partners: Methods Mol Biol. 2008;444: Protocols available 2000 online DSP MINI MINI MINI MINI MB HP MINI MINI MINI CST MIDI HP: High Pure PCR Template Preparation Kit, MINI: QIAamp DNA Blood Mini Kit, CST: CST genomic DNA purification Kit, MB: in-house magnetic bead separation method, MIDI: QIAamp DNA Blood Midi Kit Pool Nucleic acid extraction with specific magnetic Bead-Based 2 capture: critical parameters Legler TJ et al.: Manuscript submitted MD thesis completed and submitted Zhong Liu

2008;444:209-18 Protocols available 2000 online http://www.safenoe.

5 RHD NIPD Technology platforms assessed (larger scale) QIAamp Blood Kit (Qiagen, Hilden, Germany) n=851 Rouillac-Le Sciellour C et al. Mol Diagn 2004:8:23-31 MagnaPure (Roche Diagnostics, Basel, Switzerland) n=1257 Van der Schoot CE et al. Transfus Clin Biol 2006;13:53-7 Ampliprep (Roche Diagnostics) n=545 Minon JM et al. Transfusion 2008;48: MDx BioRobot (Qiagen) n=1869 Bristol, UK: Finning K et. al. BMJ 2008;336: QIAamp DSP Virus Kit (Qiagen) n=1022 Chemagen Separation Module 1 (Chemagen, Baesweiler, Germany) Göttingen, Germany: Müller SP et al. Transfusion (in press)

Transfus Clin Biol 2006;13:53-7 Ampliprep (Roche Diagnostics) n=545 Minon JM et al.

6 Fetal DNA Yield (n=620, RHD exon 7) Müller SP et al.: Transfusion (in press) DSP Virus Kit: pg/ml, median 101pg/ml Chemagen Magn. Sep. Mod.1: pg/ml, median 703pg/ml

: Transfusion (in press) DSP Virus Kit: 6

7 Diagnostic Sensitivity/Specificity NIPD Sensitivity [%] Specificity [%] Serology (Müller) 99.5 >99.7 Chemagen (Müller) MDx (Finning) MagnaPure (van der Schoot) Ampliprep (Minon) >

7 Chemagen (Müller) 99.8 98.1 MDx (Finning) 99.7 94.

8 Quality Assurance scheme The International Blood Group Reference Laboratory (IBGRL, SAFE partner no. 26)* in Bristol, UK, ( organizes RHD NIPD Workshops on behalf of the International Society for Blood Transfusion (ISPD) and the International Council for Standardization in Haematology (ICSH) every two years since 2004 (2006, 2008). Voluntary testing for other bloodgroups (RhC/c, Kell) is possible.

uk/) organizes RHD NIPD Workshops on behalf of the International Society for Blood Transfusion (ISPD) and

9 SAFE: RHD NIPD Standardisation workflow 1. A reference measurement procedure was determined 2. The reference protocol was adapted in collaborative multicenter experiments and discussion workshops 3. A reference material of a higher order for the determination of the analytical sensitivity was agreed in a workshop 4. Diagnostic sensitivity and specificity were determined for the most promising technology platforms in large-scale singlecentre studies 5. A Quality Assurance scheme for gauging levels of repeatability, consistency and uniformity was established 6. Agreement was obtained in a discussion workshop that the internal control is not mandatory for RHD NIPD screening.

A reference material of a higher order for the determination of the analytical sensitivity was agreed in a workshop 4.

12 Anti-CD19 (20x) (negative=green) Anti-CD3 (20x) (positive=red)

13 Cost-effectiveness (WP6) data kindly provided by A. Haverkamp Costs for RHD NIPD in small scale Costs for RHD NIPD in large scale Break-even Price NIPD vs. General antenatal anti-d RhD related costs now in Germany per pregancy RhD related costs with NIPD

01 Costs for RHD NIPD in large scale 24.11 Break-even Price NIPD vs.

14 Conclusions The consensus process was facilitated by travel grants, wet workshop grants, confidential agreements, and biobanking grants from the European Commission. SAFE stimulated a lot of collaborative actions, research and spreading of excellence Ongoing of funding is appreciated

15 Sina Müller, Sibylle Damme Britta Severitt, Michael Köhler Iris Bartels, Günther Emons Werner Stein, Kai Gutensohn Stan Urbaniak, Evelyn Tait Sylvia Armstrong Fisher Paul Metcalfe IBGRL/ISBT EQA scheme: Kirstin Finning, Geoff Daniels SAFE Partners: Ellen van der Schoot, Aicha Ait Soussan, Sinuhe Hahn Peter Sedelmayr, Neil Avent Acknowledgment Funding from the European Commission for the Special Non-invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence (LSHB-CT ), for which this study was partially funded, is gratefully acknowledged.

Soussan, Sinuhe Hahn Peter Sedelmayr, Neil Avent Acknowledgment Funding from the European Commission for the Special Non-invasive Advances in

Setting up a NIPD Biobank of maternal samples: Sample collection, Storage and DNA extraction protocols

Setting up a NIPD Biobank of maternal samples: Sample collection, Storage and DNA extraction protocols Tobias J. Legler Dept. of Transfusion Medicine, University Medical Center Göttingen DIN ISO 9001:2000