NHS screening programme for sickle cell and thalassemia.

This research, carried out in collaboration with Bruker UK Ltd, evaluated a newly developed mass spectrometry based method as part of a clinical trial involving 2017 patients. The bursary enabled collection, evaluation and exploitation of data from the clinical trial carried out in collaboration with the Haematology Department of University Hospitals Coventry and Warwickshire NHS Trust. In a three month mirrored trial against current clinical methods the mass spectrometry-based approaches proved to be competitive and in the trial the developed approaches were able to confidently diagnose the clinically significant variants screened for as a requirement of the NHS screening programme for sickle cell and thalassemia.

The novel top-down ETD approach employed had demonstrated significant potential for screening hemoglobinopathies prior to the period of the funding received, and in the six months of the funding a large amount of data was collected covering more than a 1000 patient blood samples. The novel mass spectrometry based method has the advantage of short sample preparation time which is of great value in a clinical laboratory involved in high throughput population screening. After a simple dilution step the method was shown to be capable of providing absolute confirmation of the monitored mutations.

The detailed structural information obtained from the mass spectrometry data is characteristic for a specific variant and cannot be obtained from current, chromatography based clinical screening techniques. A script developed for batch data processing in collaboration with our collaborator has been shown to be extremely useful for high-throughput applications allowing the automation of data analysis. The generated pdf format report is easy to read and its interpretation does not require expert staff which is also desirable for clinical laboratory applications.

In order to realize the full potential of the top-down ETD method further optimisation and technical improvements have been shown to be required. A reliable low cost sample introduction system would allow intact globin chain analysis section to be optimised for HbA2, HbA1c and HbF level estimations.

Future plans for the project involve further multi-site clinical trials in the clinical laboratories of hospitals in Coventry (UHCW) and London (Guy’s and St Thomas’). The novel technique developed in collaboration with our industrial partner shows high potential to replace the combination of currently used clinical methods. Our collaboration with industry allows access to the latest technical developments and a contract for the loan of appropriate mass spectrometry instrumentation is already in place between the University and Bruker Daltonics UK.

With the publication of the clinical results already obtained and with the addition of results on an improved system a research grant application is being prepared and will be submitted for the Medical Research Council Developmental Pathway Funding Scheme. This research grant requires an industrial partner to have been identified and will fund the further clinical trials at the different hospital sites.

The introduction of the new technology will provide additional patient benefits at reduced overall cost/test to the Health Service.

The research has been presented at the following international conferences:

Krisztina Radi, Baharak Vafadar-Isfahani, Jane Newbold, Nicholas Jackson and James H. Scrivens. Mass spectrometry-based approaches to the diagnosis of hemoglobinopathies. Warwick Mass Spectrometry 80/60 Conference, 2012, Coventry, UK

Krisztina Radi, Baharak Vafadar-Isfahani, Jane Newbold, Nicholas Jackson and James H. Scrivens. Automated quantitative mass spectrometry-based approaches for the diagnosis of beta thalassemia in a clinical trial setup. MSACL 2013 - Mass Spectrometry Applications to the Clinical Laboratory, San Diego, CA, United States

James Scrivens, Krisztina Radi, Baharak Vafadar-Isfahani, Julia Smith, Jane Newbold, Nicholas Jackson. Development of a mass spectrometry based approach for the diagnosis of hemoglobinopathies. Proc. 61st ASMS Conf. on Mass Spectrometry and Allied topics, 2013, Minneapolis, USA

Publications currently in preparation:

A publication covering the whole clinical trial is under preparation to be submitted to the Journal Blood

An evaluation of mass spectrometry-based approaches to the diagnosis of hemoglobinopathies

Krisztina Radi, Baharak Vafadar-Isfahani, Jane Newbold, Nicholas Jackson and James H. Scrivens.