Healthcare Scientists Knowledge Transfer Partnership (HCS KTP)

James Hawley, Principal Clinical Scientist, MRC Chain-Florey Clinical Research Fellow, Manchester University NHS Foundation Trust

Project title: Urine steroid metabolomics (USM) for the differential diagnosis of adrenal tumours

Adrenal tumors are detected in up to 7% of cross-sectional imaging studies, which have limited specificity for diagnosing adrenocortical carcinoma (ACC). Urine steroid metabolomics (USM), a sensitive and specific tool for detecting ACC, was first established by combining multi-steroid profiling using gas chromatography-mass spectrometry (GC-MS), a complex and labor-intensive low-throughput method, with a machine learning-based diagnostic algorithm.

To improve assay throughout, USM has been transferred to liquid chromatography-tandem mass spectrometry (LC-MS/MS) and prospectively validated in 2017 patients with adrenal masses. This has unequivocally proven that USM is superior to existing testing strategies and can significantly improve diagnostic accuracy.

Thus, implementation of this assay will improve the identification of ACC and reduce the number of unnecessary surgeries for benign adrenocortical adenoma. However, before this assay can be translated into routine practice it is necessary to improve the standardisation of the calibrators. This is essential as the accuracy of the machine learning algorithm is exquisitely dependent on the reproducibility of the calibrators.

Therefore, the primary objective of this research is to establish accurate concentrations of the calibration materials using quantitative nuclear magnetic resonance (qNMR). This will ensure results are traceable to SI units through an unbroken chain of calibration and will be essential to introducing the assay across multiple sites.

Successfully producing calibrators traceable to a higher-order methodology will also contribute towards the secondary objective of this research, that is achieving UKAS and MHRA accreditation of USM as a diagnostic test.

Zoe Barclay, Principal Clinical Scientist, Synnovis Analytics

Project title: Acylcarnitine Analysis Harmonisation: Development of Acylcarnitine Reference Materials

Acylcarnitine analysis is measured in laboratories across the country and is helpful in the evaluation of a wide-ranging patient group, including infants and neonates. The test is primarily used in order to detect and monitor a set of metabolic disorders termed fatty acid oxidation disorders and organic acidemias. This set of disorders can present with episodes of acute life-threatening illness, and are difficult to detect clinically. As such, diagnosis of these conditions is predominantly performed on the basis of laboratory results, of which acylcarnitine analysis is a key element. An effective acylcarnitine biochemical test is therefore essential for patient diagnosis and management.

An accepted limitation of the assay is a lack of commercial acylcarnitine reference materials of known value which can be used to assess the accuracy of laboratory measurement in addition to how they compare with other laboratories. There is also a wide variety of methods with which acylcarnitine analysis can be performed, all of which can contribute to a variation in results between different laboratories. The resulting lack of standardisation and harmonisation provides little reassurance as to the accuracy and commutability of acylcarnitine quantification.

This project aims, in collaboration with the National Measurement Laboratory and Medicines and Healthcare products Regulatory Agency, to produce acylcarnitine material for which the quantity of acylcarnitine is accurately determined. Furthermore, the project will aim to establish the baseline spread of acylcarnitine results between laboratories. The reference materials will then be distributed with the aim to assess whether the accuracy and harmonisation of laboratories can be improved with these materials.

The longer term vision will be to use the findings of the project to produce best practice guidelines for the analysis of acylcarnitines, which will recommend the preferred methodology and materials required for effective, precise and accurate acylcarnitine quantitation. The aim is thus to harmonise acylcarnitine measurement throughout the UK, minimising the risk of result misinterpretation, patient misdiagnosis and ultimately improving the quality and safety of patient care.

Marcus Pond, Clinical Scientist: Virology, North West London Pathology

Project title: Development of materials for CMV RNA diagnostics

This initiative aims to enhance RNA quantification methodologies for monitoring DNA virus infections during antiviral treatment by leveraging knowledge exchange between the UK’s National Measurement System (NMS) and the United Kingdom Accreditation Service (UKAS). The focus is on Letermovir, a recently approved antiviral drug for preventing Cytomegalovirus (CMV) reactivation in transplantation scenarios. However, RNA testing methodologies for monitoring CMV transcriptional activity are not widely utilised in NHS diagnostic virology services due to the lack of RNA control materials for CMV.

The project plans to collaborate with NMS and UKAS to develop and validate CMV RNA control materials mimicking CMV RNA transcription during viral reactivation. The initiative involves collaborative development, rigorous validation, expert consultation, collaborative publications, webinars, network engagement, integration into quality assurance systems, communication with UKAS, and documentation preparation.

The project anticipates the successful development and validation of CMV RNA standard materials, integration into NHS clinical virology protocols, and alignment with accreditation requirements.

By implementing this dissemination plan, the project aims to share knowledge and materials, facilitating their integration into the wider NHS clinical virology system and accreditation processes. The vision entails a transformative impact on healthcare, research, innovation, organisational efficiency, and professional advancement within the clinical virology community.

Billy Wood, Clinical Scientist, Hywel Dda University Health Board

Project : TriTech Institute and Innovation, specialising in research and evaluation of medical devices and software

The TriTech Institute at Hywel Dda University Health Board (HDUHB) are working on design and development projects with the respiratory teams in the health board to address the challenges that clinicians and patients have raised. These projects stem from patient and clinician needs, where there are no commercial solutions available, or they have been discontinued. Requests have also received from other clinicians who need solutions for specific challenges in a short time frame, including one-off solutions for patients with complex neurological disorders.

TriTech are currently collaborating with local academic partners (Assistive Technologies Innovation Centre, ATiC, part of the University of Wales, Trinity St. David) who are providing prototyping and design support and the projects are being risk managed under ISO 13485. This research aims to build upon the existing guidance from the Institute of Physics and Engineering in Medicine (IPEM) for in-house manufacture of medical devices. Developing a national framework for designing, building, and clinically testing in-house medical devices that benefit our patients in a safe and fast way, especially where there are no commercial alternatives.

The aim is to work with other partners in the NHS and collaborate with the NMS/UKAS to enhance our knowledge of how to create in-house medical devices more efficiently and quickly while showing economic and patient outcome benefits. Developing guidance that makes this process consistent will help to make sure that more health boards and trusts can acquire and use the skills and knowledge needed to make in-house devices that address unmet clinical needs.

Chris Harrington, Deputy Director SAS Trace Element Laboratory, Deputy Director UK NEQAS for Trace Elements and Peptide, Royal Surrey NHS Foundation Trust

Project : Investigation into the Feasibility of Mass Spectrometry Platforms to Improve the Traceability of Clinical Measurements

Methods based on mass spectrometry (MS) can now reach the low detection limits required for the direct measurement of clinical biomarkers, even in the presence of complex matrices. However, there has been a lack of appreciation of the merits of using the combination of organic and inorganic MS to improve clinical measurements, in particular, how their combined use can unlock greater potential for improvements in traceable measurements.

To demonstrate this potential, we will investigate a structured approach to the combination of organic and inorganic MS to underpin routine measurements in NHS laboratories. To investigate the strengths and weaknesses, we will develop a proof-of-concept based on the measurement of serum (metallo) proteins in disorders of metal metabolism with a genetic origin.

A currently available method for the measurement of serum proteins using high performance liquid chromatography (HPLC) separation, coupled to an inductively coupled plasma MS (ICP-MS/MS) detector, focused on the measurement of ceruloplasmin (CP) – the main copper containing protein in serum, which is lower in patients with Wilson disease (WD).

This method had some distinct advantages over the routine method for the measurement of holo-CP based on immunochemistry and nephelometry. At the low CP levels (<10 mg dL-1) in WD patients, the immunochemical method overestimates the concentration of holo-CP due to the high concentration of apo-CP present. This is important because the level of CP is used as part of the diagnosis of WD.

In another example of how this approach can be used, an HPLC-ICP-MS/MS method for the quantification of serum proteins by measurement of the heteroatom sulphur present in the amino acids cysteine and methionine, has shown considerable promise for the measurement of albumin in liver patients, with a low albumin present in icteric samples, which were not measurable by spectroscopic methods. In acute liver failure (ALF) patients, bilirubin levels are often high, adversely affecting measurements by routine methods. Albumin is an important indicator of liver function and is often low in ALF patients. The use of HPLC-ICP-MS/MS can accurately measure low albumin levels in the presence of bilirubin.

The aim of this work is to improve the traceability of clinical measurements, by developing methods based on inorganic MS that can be calibrated using elemental standards. Organic MS will be used to better understand the uncertainties associated with using a “generic” elemental standard as a replacement for a specific protein isoform.